United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-12/008F
Final
12-04-2012
Provisional Peer-Reviewed Toxicity Values for
Chloromethane
(CASRN 74-87-3)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Custodio V. Muianga, PhD, MPH
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Ambuja Bale, PhD, DABT
National Center for Environmental Assessment, Washington, DC
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
l
Chloromethane
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS iii
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4
HUMAN STUDIES 20
Oral Exposure 20
Inhalation Exposure 20
ANIMAL STUDIES 21
Oral Exposure 21
Subchronic-duration Studies 21
Chronic-duration Studies 21
Developmental and Reproduction Studies 21
Inhalation Exposure 21
Short-term Studies 21
Subchronic-duration Studies 25
Chronic-duration Studies 26
Developmental and Reproduction Studies 27
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 29
DERIVATION 01 PROVISIONAL VALUES 34
DERIVATION OF ORAL REFERENCE DOSES 35
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 35
Derivation of Subchronic p-RfC 35
Derivation of Chronic RfC 37
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 37
MODE-OF-ACTION (MOA) DISCUSSION 39
Mutagenicity Information 40
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 41
APPENDIX A. PROVISIONAL SCREENING VALUES 42
APPENDIX B. DATA TABLES 43
APPENDIX C. BMD MODELING OUTPUTS FOR CHLOROMETHANE 52
APPENDIX D. REFERENCES 53
li
Chloromethane
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELrec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
(III OROM I I I I AN I (CASRN 74-87-3)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (littp://www.epa.gov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
Chloromethane (also known as methyl chloride) is a colorless gas (ATSDR, 1998) with a
faint, sweet smell noticeable only at levels which may be toxic. Chloromethane is produced in
industry through reacting methanol and hydrogen chloride or chlorination of methane, but is also
formed in oceans by natural processes (e.g., marine phytoplankton) and from biomass burning in
grasslands and forest fires; it has been detected at low levels in air all over the world. Other
sources of exposure to chloromethane include cigarette smoke, polystyrene insulation, and
aerosol propellants; home burning of wood, coal, or certain plastics; and chlorinated swimming
pools. Chloromethane is also present in some lakes and streams and has been found at low levels
in drinking water.
Industrial uses of chloromethane include manufacturing of silicones, agrichemicals,
synthetic rubber, methyl cellulose, tetramethyl lead, use as thermometric and thermostatic fluid
in measurement equipment, use as a refrigerant, and use as an anesthetic (U.S. EPA, 2001).
The empirical formula for chloromethane is CH3C1 (see Figure 1). Table 1 provides a
table of physicochemical properties. In this document, "statistically significant" denotes a
p-value of <0.05.
CH3—CI
Figure 1. Chloromethane Structure
Table 1. Physicochemical Properties Table (Chloromethane)11
Property (unit)
Value
Boiling point (°C)
-23.7
Melting point (°C)
-97.6
Density (0°C, 1 atm, air = 1)
1.74
Vapor pressure (mm Hg at 25°C)
4310
pH (unitless)
Not available
Solubility in water (mg/L at 25°C)
4800-5325
Vapor density (kg/m3 at 0°C)
2.22
Molecular weight (g/mol)
50.49
Flash point (°C)
-46
Log octanol/water partition coefficient (unitless)
0.91
"Values from the U.S. EPA (2001), ATSDR (1998), and OECD (2003).
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EPA's IRIS database (U.S. EPA, 2011) reports a noncancer chronic inhalation reference
concentration (RfC) for chloromethane of 0.09 mg/m3 based on cerebellar lesions in female
C57BL/6 mice exposed continuously (22-22.5 hours/day) for 11 days. The IRIS report states
that an oral reference dose (RfD) is not applicable because chloromethane exists primarily as a
gas and because no adequate oral exposure studies exist from which an oral RfD may be derived.
The IRIS data were last revised on July 17, 2001, and a review of more recent toxicological
literature conducted in August 2003 did not identify any new critical studies. IRIS has not
derived a quantitative estimate of carcinogenic risk from oral or inhalation exposure, and
provided a weight-of-evidence descriptor of Group D ("Not Classifiable as to its Human
Carcinogenicity") (U.S. EPA, 2001).
Chloromethane is not included in the National Toxicology Program's 12th Report on
Carcinogens (NTP, 2011). Also, chloromethane is considered "Not Classifiable as a Human
Carcinogen" based on inadequate data in humans and/or animals and is, therefore, categorized as
A4 by the American Conference of Governmental Industrial Hygienists (ACGIH, 2001) and in
Group 3 by the International Agency for Research on Cancer (IARC, 1999). However, the
National Institute of Occupational Safety and Health (NIOSH, 2005) considers chloromethane to
be a potential occupational carcinogen. CalEPA (2008, 2009a,b) has not derived toxicity values
for chloromethane.
The Drinking Water Standards and Health Advisories List (U.S. EPA, 2006) reports an
RfD of 0.004 mg/kg-day, a Drinking Water Exposure Limit (DWEL) of 0.1 mg/L, and a
life-time health advisory (HA) of 0.03 mg/L for chloromethane. Chloromethane has a
time-weighted average threshold limit value (TLV-TWA) of 50 ppm (103 mg/m3) and a
short-term exposure limit (STEL) of 100 ppm for occupational exposures to chloromethane in
workplace air (ACGIH, 2001; WHO, 2010). The Occupational Safety and Health
Administration (OSHA, 2006) permissible exposure limit (PEL) values are a 100-ppm TWA and
a 200-ppm acceptable ceiling concentration, with a 5-minute maximum peak of 300 ppm in any
3-hour period. The ATSDR (2010) reported an acute inhalation Minimal Risk Level (MRL) of
0.5 ppm derived from a NOAEL of 50 ppm for motor coordination and damage to the cerebellar
granule cells in a study by Landry et al. (1983, 1985), and an intermediate MRL of 0.2 ppm
derived from a LOAEL of 51 ppm for increased liver enzymes in male mice at the 6-month
interval in the 2-year study by CUT (1981), and a chronic MRL of 0.05 ppm derived from a
LOAEL of 51 ppm for axonal swelling in male mice in the same study by CUT (1981). The
World Health Organization (WHO, 2010) published the Concise International Assessment
Document 28 with a guidance value for indirect inhalation exposure to methyl chloride via the
environment for the general population of 0.018 mg/m3 (0.009 ppm) and a guidance value for
occupational inhalation exposure of 1.0 mg/m3 (0.5 ppm) (WHO, 2000).
Literature searches were conducted for studies from 1900 through May 2011 relevant to
the derivation of provisional toxicity values for chloromethane, CAS No. 74-87-3. Searches
were conducted using EPA's Health and Environmental Research Online (HERO) database of
scientific literature. HERO searches the following databases: AGRICOLA; American Chemical
Society; BioOne; Cochrane Library; DOE: Energy Information Administration, Information
Bridge, and Energy Citations Database; EBSCO: Academic Search Complete; GeoRef Preview;
GPO: Government Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan Science &
Technology; JSTOR: Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA
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publications available through the National Service Center for Environmental Publications
[NSCEP] and National Environmental Publications Internet Site [NEPIS] database); PubMed:
MEDLINE and CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink;
TOXNET (Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART,
EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS,
ITER, LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and
TSCATS; Virtual Health Library; Web of Science (searches Current Content database among
others); World Health Organization; and Worldwide Science. The following databases outside
of HERO were searched for health-related values: ACGIH, ATSDR, CalEPA, EPA IRIS, EPA
HEAST, EPA HEEP, EPA OW, EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides information for all of the potentially relevant studies. Entries for the
principal studies are bolded. Because a chronic RfC is available in IRIS, a subchronic p-RfC is
developed here. The majority of the information in this PPRTV document is obtained from the
Toxicological Review of Methyl Chloride: in Support of Summary Information on the Integrated
Risk Information System, EPA/635/R01/003 (U.S. EPA, 2001). The studies included in the
toxicological review for IRIS are listed in Table 2 but are not described in detail in the following
section of this document. The study descriptions are limited only to those details necessary to
demonstrate the selection of the principal study for the derivation of a provisional toxicity value.
In contrast, the few studies not included in the toxicological review, and those published
subsequent to the latest revision in IRIS, are detailed in the appropriate sections. Specifically,
summaries of studies by Lof et al. (2000), Jonsson et al. (2001), and Asakura et al. (2008) are
detailed in the section on "Other Data (Short-term Tests, Other Examination)," and a study by
Kernan et al. (1999) is included in the sections discussing human inhalation toxicity and cancer
weight of evidence. Additionally, these studies are summarized in an Addendum to the
Toxicological Profile for Chloromethane (ATSDR, 2009).
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Human
1. Oral (mg/kg-day)b
Subchronic
None
Chronic
None
Developmental
None
Reproductive
None
Carcinogenic
None
2. Inhalation (mg/m3)b
Short-term
9/9 workers (sector not
specified), occupational
epidemiological study
1-7.5 hr/dfor2 dor
7.5 hr/d for 5 d in a wk
0, 2, 9, 13 or
0, 13, 65, 97
No significant neurological or
cognitive abnormalities were
observed.
Two to six times higher blood
and breath chloromethane levels
97d
Not run
Not observed
Stewart et al.
(1980)
U.S.
NIOSH
Report
56 humans (39/17)
divided in 8 or 12 per
group, clinical study, 3 hr
0, 26 (behavioral effects
not examined), 52 with
or without concurrent
ingestion of 10 mg of
diazepam
Marginal (p = 0.053) decrease
of 4% in performance tasks
(visual vigilance and time
discrimination)
Not
established6
Not run
52d
Putz-Anderson
et al. (1981)
PR
5
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Short-term
24 workers accidentally
exposed to leaking
refrigeration unit ranged
from 2 to 4 d; mortality
and cancer retrospective
occupational
epidemiological study,
32-yr follow-up
Concentration not
measured; groups
divided into the
deckhands with direct,
longer term exposure
(15/17 displayed signs
of toxicity within 2 d of
exposure) compared to
11 other crewman with
minimal exposure
(officers and those with
quarters further from
leak)
Excess mortality more
prominent among deckhands
who had been subjected to
higher exposure; risk ratios
(RR) elevated for all causes of
death (2.5), as well as for
cardiovascular diseases (3.9).
However, elevated RR for all
cancers (1.5) and lung cancer
(2.7) had wide confidence
intervals, which included unity,
and do not appear to be
suggestive of an elevated cancer
mortality risk
Not applicable
Not run
Not applicable
Rafnsson and
Gudmundsson
(1997)
PR
Subchronic
6 workers (4 male;
2 unspecified), exposed
for at least 2-3 wk prior to
the onset of symptoms);
occupational case studies,
duration not specified
Cases 1 and 2,
8 hr TWA < 148
Cases 3 through 6,
8 hr TWA 130
Calculated from 8 hr/d,
5 d/wk, 2-wk exposure
Central nervous system (CNS)
toxicity (confusion, blurry
vision, short-term memory
deficits, balance instability,
hand tremor, slurring of speech,
and loss of concentration)
Not established
Not run
130d
Dow Chemical
Company
(1992a)
NPR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Chronic
114/8 exposed workers
and 46/3 not exposed
workers, occupational
epidemiological study,
duration of exposure
ranged from 4 mo to 25 yr
of employment
Range between
5-48 mg/m3 with an
average of 23 mg/m3
(via conductivity
analyses); 31 mg/m3 via
charcoal tube sampling
during week of testing
Changes in performance on
cognitive time-sharing tasks and
increased magnitude of finger
tremor
Not applicable
Not run
Not applicable
Repko et al.
(1976)
Concentration
only measured
during week of
testing and not
for entire
potential
exposure period
(up to 25 yr);
therefore
precludes
meaningful
quantitative
assessment
NPR
NIOSH
Report
2610 white male workers
working at Dow Chemical
Company between 1956
and 1980; retrospective
occupational study, mean
of 8.3 yr of employment
(range of 1 to 20+ yr).
Mean number of years
follow-up was 10.5 yr
Concentration not
measured
Nonsignificant increases in
cancers of brain and CNS;
increased mortality due to
leukemia and aleukemia
(however, there were only
3 cases, and they were not of
similar histology) (chronic
granulocytic, acute
lymphoblastic, and acute
aleukemic myeloid), exposure
duration (9.8, 1.2, and 2.8 yr),
or job title (chemical analyst,
chemical engineer, and
mechanical engineer)
Not applicable
Not run
Not applicable
Olsen et al.
(1989)
Exposure to
other chemicals
(22 were listed)
at Dow
Chemical
Company
during this time
frame
confounded
interpretation
PR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Chronic
Follow-up case control
study of respiratory
cancers at one of Dow
Corning Corporation's
silicone production plants,
an area specific for
chloromethane exposure;
no further information
(e.g., sample size or study
design) was provided in
toxicology review
(U.S. EPA, 2001)
Concentration not
measured
No association between
exposure and respiratory cancer
risk was found
Not applicable
Not run
Not applicable
Dow Chemical
Company
(1992b). High
prevalence of
smoking noted
as a
confounding
factor
NPR
Retrospective
occupational
epidemiological study of
852 males employed in a
synthetic rubber
manufacturing plant from
at least 1 mo to 35 yr
during 1943-1978
Exposure levels (high,
medium, low) based on
process description, list
of job titles and
associated locations,
duties, and activities
associated with job
titles, and information
from workers and
personal experience. No
additional information
was reported
No excess mortality from any
specific cause of death found in
the study population after
analysis by level and duration of
exposure; some groups actually
showed lower incidences of
cancer due to "healthy worker"
effect
Not applicable
Not run
Not applicable
Holmes et al.
(1986)
PR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Chronic
Population-based
case-control study on
63,097 persons who died
from pancreatic cancers
from 1984-1993
compared to 252,386
individuals who died from
causes other than cancer
during the same time
period
Concentration was not
measured. A job-
exposure matrix (JEM)
was developed for each
individual solvent, and
the risk for each was
estimated by levels of
probability of exposure
(low, medium, and high
vs never exposed to the
solvent)
No association of pancreatic
cancers with exposure to
chloromethane
Not applicable
Not run
Not applicable
Kernan et al.
(1999)
PR
Developmental
Mother exposed during
pregnancy to
chloromethane and
ammonia
Concentration not
measured
Single case of an infant born
with sacral agenesis
Not applicable
Not run
Not applicable
John et al.
(1984) citing
Kucera (1968).
Confounded by
exposure to
ammonia
PR
5 pregnant females
exposed to chloromethane
and other industrial
chemicals
Concentration not
measured
Association of sacral agenesis in
five infants born to mothers
having close contact during
pregnancy to "trichloroethylene
and chloromethane, among
other industrial chemicals..."
Not applicable
Not run
Not applicable
Schardein
(1993) citing
Kucera (1968)
Confounded by
exposure to
other chemicals
PR
Reproductive
Former workers (female,
number not specified) in a
New Mexico
microelectronics assembly
plant; 90 worker-referent
pairs
Concentration not
measured
Increased risk of spontaneous
abortion in former workers
Not applicable
Not run
Not applicable
Huel et al.
(1990)
Confounded by
exposure to
other chemicals
PR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Animal
1. Oral (mg/kg-day)b
Subchronic
Rabbit (sex and strain not
specified)
2 (one per dose group);
dosed via gavage in olive
oil with 60 doses over
83-85 d
28, 71 mg/kg-d
Spleen enlarged and dark-
colored, microscopically
displayed moderate congestion,
phagocytosis, and slight
hemosiderosis. No other effects
were reported
28d
Not run
71d
Dow Chemical
Company
(1982)
Too few
animals for
meaningful
interpretation;
no control
group
NPR
Chronic
None
Developmental
None
Reproductive
None
Carcinogenic
None
2. Inhalation (mg/m3)b
Short-term
C57BL/6 mouse
0/12, whole body
continuous
(22-22.5 hr/d) exposure
for 11 d
0,28.4, 94.6,189.3,
283.9, 378.6, or 757.2
Degenerative changes in
granule cells of the cerebellum
Decreased glycogen content in
liver
94.6
Not run
189.3
Landry et al.
(1983,1985)
PS
IRIS
0/12, whole body
intermittent (5.5 hr/d)
exposure for 11 d
0,71.0, 189.3, 378.6,
757.2, or 1135.8
Cerebellar incidence of
granule-cell pyknosis and
karyorrhexis
189.3
Not run
378.6
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Short-term
20/20 Sprague-Dawley
rats, continuous exposure
for 72 hr (3 d) with a
follow-up period of 12 d.
Another 20/20, continuous
exposure for 48 hr (2 d)
with a follow-up period of
12 d
0,413, 1033,2065, or
4130
Liver effects at 72 hr (decreased
weight, altered tinctorial
appearance, and increased
amount of fat)
Testicular effects at 72 hr
(atrophy and epididymis
degeneration, inflammation,
sperm granuloma formation,
scarring, and obstructive
changes)
Not established
413
Not run
413
1033
Dow Chemical
Company
(1981)
NPR
Beagle dog and cat (strain
not specified)
3/0 each species
23.5 hr/d, for 3 d with a
follow-up period of 26 d
0, 404, 1011
Clinical signs of neurotoxicity
and histopathological lesions in
the brain and spinal cord in dogs
and cats
404
Not run
1011
McKenna et al.
(1981a)
NPR
10/10 F344 rat,
6 hr/d, for 5 d, and for
another 4 d after a 2-d
break
0, 845, 1478, and 2112
Renal, hepatic, and
testicular-related degeneration
Cerebellar degeneration
Not established
1478
Not run
845
2112
Morgan et al.
(1982)
PR
Mouse (three strains:
C3H, C57BL/6, B6C3F0
5/5
6 hr/d, for 12
consecutive d
0, 258,516, or 1033
Hepatocellular degeneration
Cerebellar degeneration
Not established
258
Not run
258
516
C57BL/6 mouse
0/10
6 hr/d, 5 d/wk, for 2 wk
0,553
Cerebellar lesions, including
degeneration, coagulative
necrosis, nuclear condensation,
focal malacia, karyorrhexis, and
edema
Not established
Not run
553d
Jiang et al.
(1985)
PR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Subchronic
CD-I mouse
10/10
6 hr/d, 5 d/wk, during a
93-95 d period (a total of
64-66 exposures)
0, 18, 54, or 144
No unequivocal toxic effects
observed. Decreased
performance on wire-maneuver
test at 54 mg/m3 for Days 40-66
and at 144 mg/m3 for Days
16-39 and 40-66. However,
this was not corroborated by
other neurological deficits;
authors attributed effects to
general muscle weakness and
confounding due to increasing
body weight with time
144
Not run
Not observed
McKenna et al.
(1981b)
NPR
Sprague-Dawley rat
10/10
6 hr/d, 5 d/wk, during a
93-95 d period (a total of
64-66 exposures
0, 18, 54, or 144
None observed
144
Not run
Not observed
Beagle dogs
4/0
6 hr/d, 5 d/wk, during a
93-95 d period (a total of
64-66 exposures)
0, 18, 54, or 144
None observed
144
Not run
Not observed
B6C3Fi mouse
10/10
6 hr/d, 5 d/wk, for 13 wk
0, 138, 277, or 553
Increased relative liver weights
138
Not run
277
Mitchell et al.
(1979a)
NPR
F344 rat
10/10
6 hr/d, 5 d/wk, for 13 wk
0, 138, 277, or 553
Decreased body weights,
vacuolar changes in hepatocytes
138
Not run
277
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Chronic
B6C3FJ mouse
120/120
6 hr/d, 5 d/wk, for 2 yr
0, 18, 83, or 368
Mortality; clinical signs of
neurotoxicity (hunched posture,
tremor, and paralysis); liver
toxicity (hepatocellular
vacuolization, karyomegaly,
cytomegaly, and degeneration
and increased ALT); kidney
effects in males (renal
tubuloepithelial hyperplasia,
hypertrophy, and/or
karyomegaly); cerebellar
(degeneration and atrophy of the
granular layer); seminiferous
tubule atrophy and
degeneration; splenic atrophy;
and lymphoid depletion
83
Not run
368
Frank effect
level (FEL) due
to high
treatment-
related
mortality
CUT (1981),
final report
Mitchell et al.
(1979b),
interim report
NPR
Carcinogenicity
368-mg/m3 males had renal
benign and malignant tumors
and renal cortical
tubuloepithelial hyperplasia and
karyomegaly
At 83 mg/m3, two renal
adenomas in males, equivocal as
to treatment-related status
83
Not run
368
FEL due to
high treatment-
related
mortality
NPR
Chronic/
Carcinogenicity
F344 rat
120/120
6 hr/d, 5 d/wk, for 2 yr
0, 18, 83, or 368
Decreased overall body-weight
gain; effects in testes
(degeneration and atrophy of the
seminiferous tubules, interstitial
hyperplasia, sperm granulomas)
83
Not run
368
CUT (1981),
final report
Mitchell et al.
(1979b),
interim report
NPR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Developmental
F344 rat
0/25
6 hr/d, Gestation Day
(GDs) 7-19
0, 52, 258, or 774
Decreased maternal and fetal
body weights and delayed
ossification
258
Not run
774
Wolkowski-
Tyl et al.
(1983a)
PR
B6C3Fi mouse
0/33
6 hrs/day from GDs 6-17
0, 52, 258, or 774
Heart malformations in fetuses
Frank effect level at 774, early
termination due to moribundity;
necrosis in cerebellum
52
Not run
258
C57BL/6 mouse
0/74-77 females/exposure
6 hr/d from GDs 6-17
0, 129, 258, or 387
Developmental: heart
malformations in fetuses
Maternal: mortality, ataxia,
convulsions, tremors,
hypersensitivity to sound or
touch, decreased body weights
Developmental:
129
Maternal: 258
Not run
Developmental:
258
Maternal: 387
Wolkowski-
Tyl et al.
(1983b)
PR
Reproductive
two-generation
reproduction
F344 rat
40/80
6 hr/d, 5 d/wk, for 10-wk
premating, 6 hr/d, 7 d/wk
for 2-wk mating period,
and throughout gestation
and lactation (except from
GD 18 to Postnatal Day 4)
0,59, 186, or 589
Decreased male fertility at
186 mg/m3
Degeneration and atrophy of
seminiferous tubules,
epididymal granulomas, and
decreased testes size
59
186
Not run
186
589
Hamm et al.
(1985)
PR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Reproductive
Rat (strain not specified)
40/0
6 hr/d, for 5 consecutive d,
not exposed for 3 d, and
exposed again for 4 d. Six
or eight treated and two
control animals were
euthanized on Days 5, 7,
9, 11, 13, 15, 19, and 70
after starting exposures
0 or 1359
Bilateral epididymal
granulomas
Not established
Not run
1359d
Chapin et al.
(1984)
PR
F344 rat
40/0
6 hr/d, for 5 consecutive d,
then bred weekly for 8 wk
with untreated females
0,516, or 1549
Increased pre- and
postimplantation loss
516
Not run
1549
Working et al.
(1985a)
PR
F344 rat
40/0
6 hr/d, for 5 consecutive d,
then bred weekly for 4 wk
with untreated females
0,516, or 1549
Increased unilateral and bilateral
sperm granulomas in
epididymides; decreased testes
weights; sperm cytotoxicity
(delayed spermiation, chromatin
margination in round
spermatids, epithelial
vacuolation, luminal exfoliation
of spermatogenic cells, and
multinucleated giant cells);
decreased sperm motility, and
increased incidence of sperm
abnormalities
516
Not run
1549
Working et al.
(1985b)
PR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Reproductive
F344 rat
30/0, 10/0, and 20/0 per 0,
516, and 1549 mg/m3,
respectively,
6 hr/d, for 5 consecutive d,
then bred weekly for 8 wk
with untreated females.
Females euthanized 12 hr
postulating, and embryos
and ova were scored as
unfertilized or fertilized
0,516, or 1549
Distinguished that increased
preimplantation loss due to
failure of fertilization
(cytotoxicity) and not
embryonic death due to
genotoxicity
516
Not run
1549
Working and
Bus (1986)
PR
F344 rat
20/0 (controls), 40/0
(treated),
6 hr/d, for 5 consecutive d
with or without
cotreatment with
anti-inflammatory agent
(BW 755C)f, a Burroughs
Wellcome experimental
compound, then bred
weekly for 3 wk with
untreated females
0 or 1549 with or
without i.p. injection of
BW 755C
Increased postimplantation loss
in treated group; however,
cotreatment with
anti-inflammatory agent
(BW 755C) prevented effects.
Concluded that the cytotoxicity
in epididymis was prevented by
blocking inflammatory response
Not established
Not run
1549
Chellman et al.
(1986a)
PR
F344 rat
12/0 (chloromethane
without B W 755C);
6 males (chloromethane
with cotreatment with B W
755C) for 6 hr/d, for 2 d
0 or 3872
Mortality and epididymal
granulomas; however,
cotreatment with
anti-inflammatory agent
(BW 755C) prevented effects
Not established
Not run
3872d
Chellman et al.
(1986b)
PR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Reproductive
F344 rat
5/0 at 2581 mg/m3, for 6
hr/d, for 5 d, with or
without cotreatment with
BW 755C
0 or 2581
Degenerative changes in testes
and epididymides (including
formation of epididymal sperm
granulomas), necrosis of the
inner granular layer of the
cerebellum, hepatocellular
cloudy swelling, degeneration
of renal proximal convoluted
tubules, vacuolar degeneration
in the adrenal cortex
Except for adrenal tissue, the
above listed tissues showed
virtually no evidence of lesions
in animals cotreated with
BW 755C
Not established
Not run
2581d
Chellman et al.
(1986b)
PR
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Table 2. Summary of Potentially Relevant Data for Chloromethane (CASRN 74-87-3)a
Exposure
Conditions or
Toxicity Study
Type
Species, Number of
Male/Female, and
Duration of Exposure
Dosimetryb
Conclusions and Major
Findings
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes0
Reproductive
F344 rat
18/0 per concentration,
6 hr/d, for 5 consecutive d
with or without
cotreatment with B W
755C 12 hr pre- and
postexposure
(6 euthanized weekly for
3 wk)
0 or 1549
Decreased relative testes
weights, testicular
histopathology, and decreased
sperm production; these effects
were not prevented by B W
755C
Sperm transit times and
epididymal sperm depletion
indicated that effects on
preimplantation loss noted in
previous studies were likely due
to cytotoxic effects on sperm in
the testes at the time of
exposure
Not established
Not run
1549d
Chellman et al.
(1987)
PR
aWiththe exception of Kernanet al. (1999), all of the studies listed in Table 2 are included in the Toxicological Review of Methyl Chloride: in Support of Summary
Information on the Integrated Risk Information System (U.S. EPA, 2001).
dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects and a human equivalent
concentration (HEC in mg/m3) for inhalation noncancer effects. Values are converted to a human equivalent dose (HED in mg/kg-d) for oral carcinogenic effects and a HEC
for inhalation carcinogenic effects. All long-term exposure values (4 wk and longer) are converted from a discontinuous to a continuous (weekly) exposure. Values from
animal developmental studies are not adjusted to a continuous exposure.
°IRIS = Utilized by IRIS, date of last update July 17, 2001; PS = principal study, NPR = not peer-reviewed, PR = peer-reviewed.
dNot reported by the study author but determined from data.
eThe study subjects in the 26-mg/m3 group were not subjected to behavioral tests; therefore, a NOAEL is not established in this study.
fBW755C = cyclooxygenase/lipoxygenase inhibitor 3-amino-1 -|/w-(trifluoromcthvl)phcnvl |-2-pyrazoline.
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HUMAN STUDIES
Oral Exposure
No studies on the effects of oral exposure of humans to chloromethane were identified.
Inhalation Exposure
Chloromethane acts principally as a depressant of the central nervous system (CNS).
Exposure situations typically have been related to accidental overexposure resulting from leaking
refrigerators or refrigeration systems. Signs and symptoms typically appear within 2-3 hours of
exposure and include headache, nausea, vomiting, painful neck, loss of appetite, diarrhea,
dizziness, giddiness, blurred vision, ataxia, confusion, slurred speech, diplopia (double vision),
tremors of the hands and lips, drooping eyelids and eye twitch, muscle spasms, convulsions and
opisthotonus (body spasms), cold and clammy skin, loss of memory, hallucinations, respiratory
depression, unconsciousness, coma, and death (U.S. EPA, 2001). Effects of longer-term,
low-level exposure are thought to be generally, although not always, mild and reversible after a
recovery period of days to months, and include fatigue or malaise, loss of appetite, headache,
disequilibrium, blurred vision, confusion, anxiety, personality changes, short-term memory loss,
vertigo, loss of coordination, weakness, pale skin, nausea, and vomiting. Evidence suggests that
in persons exposed to doses of chloromethane sufficient to cause serious CNS effects, other
organ systems including the heart, gastrointestinal tract, liver, kidneys, and lungs can be
adversely affected, although the cardiovascular and gastrointestinal effects may largely be
secondary to CNS toxicity (U.S. EPA, 2001).
The literature contains a number of other, mostly older, case reports and human studies
that have been previously summarized (U.S. EPA, 2001). They provide descriptions of the CNS,
cardiovascular, hepatic, and renal effects that can be caused in humans by exposure to
chloromethane. Most exposures appear to have been acute and of unknown duration;
chloromethane concentrations may have generally been known to be high or low but rarely were
quantified. Although some effects were noticeable within hours or a day or two of exposure and
resolved within days or several months of the cessation of exposure, in some cases, the effects
appeared to persist for years, and rarely, for the lifetime of the individual.
An epidemiological study by Kernan et al. (1999)—not included in the IRIS toxicological
review (U.S. EPA, 2001)—is summarized below. An extensive population-based case-control
study to determine which industries may be related to an increased risk of pancreatic cancers was
conducted. Death certificates of 63,097 persons who had died from pancreatic cancer in
24 U.S. states from 1984-1993 were obtained, and the occupations of these persons were
determined. The control group was composed of 252,386 persons who died from causes other
than cancer during the same time period. The National Cancer Institute, National Institute for
Occupational Safety and Health, and the National Center for Health Statistics supported the
coding of occupation and industry on death certificates from the 24 participating states. The
coding of the occupation and industry on death certificates was performed according to the
classification system designed for the 1980 U.S. census. Overall, 509 occupation codes and
231 industry codes were screened in these data. The International Classification of Disease
(ICD, 9th Rev.) was used to code the underlying cause of death. To evaluate the effects of
exposure to specific solvents, a job-exposure matrix (JEM) was applied. Industrial hygienists
developed JEMs for formaldehyde and 11 chlorinated hydrocarbons, including chloromethane.
Concentrations were not measured; however, the risk for each solvent was estimated by levels of
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probability of exposure (low, medium, and high vs. never exposed to the solvent). Odds ratios
(ORs), reported for each exposure intensity according to race and gender, ranged from 0.7-1.1,
indicating no association of pancreatic cancer with exposure to chloromethane.
ANIMAL STUDIES
Oral Exposure
Subchronic-duration Studies
No subchronic-duration oral studies on chloromethane have been located, with the
exception of a single gavage study using only two rabbits (one/dose group) and no control group
(Dow Chemical Company, 1982). The Dow Chemical Company (1982) dosed two rabbits (sex
and strain not specified) with cold olive oil solution by means of a stomach tube each work day
until 60 doses. One animal received 60 doses of chloromethane (purity not specified) at
40 mg/kg in 85 days and showed no signs of toxic effects. Another rabbit received 60 doses at
100 mg/kg in 85 days. This animal showed a very slight pathology of the spleen as evidenced by
congestion, phagocytosis, and hemosiderosis. The authors reported that it was not practical to
feed larger doses because the volume of oil would become too large, and the rapid escape of the
gas from the oil in the stomach would cause considerable blasting. Although effects were
observed in the spleen, the deficiencies of the study design, sample size, and data reporting do
not allow to draw conclusions regarding subchronic oral toxicity of chloromethane in rabbits.
Chronic-duration Studies
No chronic oral studies were identified.
Developmental and Reproduction Studies
No developmental or reproductive toxicity studies via oral exposure were identified.
Inhalation Exposure
Short-term Studies
Landry et al. (1983, 1985), Dow Chemical Company (1981), McKenna et al. (1981a),
Morgan et al. (1982), and Jiang et al. (1985) conducted short-term inhalation toxicity studies of
chloromethane in the mouse, rat, dog, and cat using exposure durations ranging from 48 hours to
12 days. A brief summary of each of these short-term inhalation studies, followed by the
subchronic-duration inhalation studies, is included below in order to demonstrate the reasoning
leading to the selection of the principal study for deriving the subchronic p-RfC. Further details
of these studies are available in the Toxicological Review of Methyl Chloride: in Support of
Summary Information on the Integrated Risk Information System (U.S. EPA, 2001).
The study by Landry et al. (1983,1985) is selected as the principal study for
deriving the subchronic p-RfC because it provides the most sensitive endpoint (lowest
POD) compared with each of the other relevant short-term- and subchronic-duration
studies. Landry et al. (1983, 1985) exposed female C57BL/6 mice (12/group; about 10 weeks
old at time of exposure) "continuously" (22-22.5 hours/day) to 0, 15, 50, 100, 150, 200, or
400 ppm (0, 28.4, 94.6, 189.3, 283.9, 378.6, or 757.2 mg/m3), or "intermittently" (5.5 hours/day)
to 0, 150, 400, 800, 1600, or 2400 ppm (0, 71.0, 189.3, 378.6, 757.2, or 1135.8 mg/m3) of
chloromethane (purity = 99.5%) for whole body during 11 days. Exposures were interrupted
once in the morning and once in the afternoon in order to move intermittently exposed mice in
and out of the exposure chambers, observe all animals, and train or test animals.
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Neurofunctional testing was conducted during the course of the study, which consisted of
monitoring mice (previously trained for 2 weeks on the apparatus) for their abilities to stay on an
accelerating rod (acceleration = 1 rpm/second, from 10 rpm up to 70 rpm) 2-2.5 hours
postexposure after 4, 8, and 11 days of exposure. Upon termination, the nonfasted mice were
subjected to gross and histopathological examination (i.e., brain, thymus, liver, and kidneys).
Body and organ weights were obtained, as were samples of most major organs and tissues
(including spinal cord). Tissue samples from the cerebella of three preselected mice from each
of the 0- and 150-ppm continuously exposed groups were examined by electron microscopy after
1, 2, 4, 6, 8, or 10.5 days of exposure.
In the continuous exposure groups (Landry et al., 1983, 1985), no exposure-related
mortality was observed at the lower concentrations (15 and 50 ppm), whereas exposure to 200 or
400 ppm was lethal after 5 or 4 days, respectively. Death was preceded by loss of appetite and
ataxia with frequent falling. Mice exposed to 150 to 400 ppm developed poor motor
coordination and deteriorated to a moribund condition with accompanying inanition (the
exhausted condition that results from lack of food and water) (i.e., marked weakness) at a rate
that was dose dependent. Mice in the 200-ppm group were sacrificed on Day 5 because one
mouse died prior to scheduled necropsy, and most of those remaining were moribund. Mean
body weights were significantly (p < 0.05) decreased by 12-34% at 150 and 200 ppm and
slightly decreased by 4-7% at 100 ppm but were not affected at <50 ppm (see Table B. 1). Body
weights were not obtained for the 400-ppm mice. No significant decrements in rotating-rod test
performance were noted for the control and 15- to 100-ppm groups; however, at 150 ppm,
rotating-rod test performance was decreased (p < 0.05) by 59% on Day 4 and by 74% on Day 8,
with animals moribund or dead by Day 11 (see Table B.2). All mice at 200 ppm, the majority of
which were moribund, scored zero in this test.
No organ-weight data were reported for the 200- and 400-ppm groups (Landry et al.,
1983, 1985). Mean relative (but not absolute) kidney weights were increased by 9% at 150 ppm
compared to controls (no increase at Day 8) but not at 50 and 15 ppm (see Table B.3).
Kidney-weight data were not obtained for the 100-ppm group. Absolute liver weights at
150 ppm were decreased by 13% (p < 0.05) compared to controls. Absolute and relative thymus
weights were significantly (p < 0.05) decreased by 21—23% at 50 and 15 ppm, respectively, and
by 69-71%) at 150 ppm. However, the decreased thymus weights at 15 and 50 ppm were
considered unrelated to treatment because they lacked corroborating histopathology data, and the
values fell within the range of other control groups in this study (i.e., the control group run
concurrently with the 100-ppm group). The decrease at 150 ppm was considered exposure
related, with the only histopathological finding being thymic involution (7 out of 12 minimal and
5 out of 12 marked), reflecting decreased body weights and stress.
Gross pathology observations included significant inanition in the 200- and 400-ppm
mice prior to death or sacrifice, and in some 150-ppm mice after >4 days of exposure. No
treatment-related gross pathology was observed at 15, 50, or 100 ppm. Exposure to 100 ppm and
above resulted in concentration- and duration-dependent degenerative changes to the cerebellum,
principally in the granule cells, which were characterized by nuclear pyknosis and karyorrhexis,
the latter referring to the rupture of the cell nucleus in which chromatin disintegrates (see
Table B.4). These effects were observed most frequently in the dorso-medial cerebellar folia.
Lesions were more severe at 200 and 400 ppm. Transient intra- and extracellular vacuolation in
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the Purkinje and/or molecular cell layer, and in the white matter, was also noted. Electron
microscope observations were consistent with those obtained through light microscopy.
Duration-dependency of cerebellar lesions was examined by serial necropsy of 150-ppm animals
on Days 1, 2, 4, 6, 8, and 11 (see Table B.5). At 150 ppm, there was a marked loss of granule
cells, a decrease in Purkinje cells, and an increase in macrophages. Decreased glycogen content
at 100-400 ppm was the principal significant change observed in the liver, although focal
periportal hepatocellular degeneration and/or necrosis was also noted at 400 ppm (see
Table B.4). No statistical test was performed with the data in Tables B.4 and B.5. No
exposure-related histopathological effects were observed at 15 or 50 ppm.
In the intermittent exposure groups, (Landry et al., 1983, 1985), transient (i.e., at
0.5 hours, but not 3 hours, postexposure) sedation was observed in 1600- and 2400-ppm groups
at 4-7 days of exposure but not after 8 days. Inanition was apparent in the 2400-ppm group
(also slow movement and roughened haircoats), as was thin, watery blood from the heart, a
finding supported by low hematocrit values. The spleens of this group were considerably
enlarged. This was suggestive of extramedullary hematopoiesis, which was microscopically
confirmed. The in-life observation of red urine at 2400 ppm was determined to result from
hemoglobinuria consistent with intravascular hemolysis (hemoglobinemia) rather than from
hematuria. These animals deteriorated (e.g., hind limb extensor rigidity) and were euthanized in
moribund condition on Days 8-9. Decreased ingesta was noted at 1600 ppm. Severe clinical
signs of toxicity were observed at 1600 ppm, including slightly rigid hind limbs, some tendency
toward rearing on hind legs (2 out of 12), and greater excitability compared to controls; these
effects tended to mitigate during overnight periods of nonexposure. Mean body weights were
significantly (p < 0.05) decreased by 8-16% at 2400 ppm but were not affected at lower
concentrations (see Table B.l). Compared to controls, rotating-rod test performance was
significantly decreased by 15% at 800 and 1600 ppm on Day 4, by 36% at 2400 ppm on Day 4,
and by 84% at 2400 ppm on Day 8 (see Table B.2). No significant decreases in rotating-rod test
performance were noted after intermittent exposure to 150- or 400-ppm chloromethane.
Relative (but not absolute) kidney weights were increased by 19% (not significant) in the
2400-ppm group compared to controls but were not increased at 150 ppm (see Table B.3).
Kidney-weight data were not obtained for the 400-, 800-, or 1600-ppm groups. Microscopically,
evidence of kidney toxicity was found only at 2400 ppm, and consisted of slight multifocal
tubular degeneration and regeneration and eosinophilic-staining tubular casts. Absolute and
relative liver weights at 1600 ppm were significantly (p < 0.05) increased by 23% over the
control group. Decreased hepatocyte size, without degeneration or necrosis, was variable in
mice from the 400- through 2400-ppm groups (see Table B.6). Decreases in mean absolute and
relative thymus weights were statistically significant and considered treatment related (reflecting
decreased body weights and stress) at 1600 (39-40% decrease) and 2400 (87—89% decrease)
ppm (see Table B.3.), with a decrease in the size of the thymus noted at 1600 ppm. No
treatment-related macroscopic findings were noted at 400 or 800 ppm. A concentration-related
increase in the incidence of pyknosis and karyorrhexis (slight) of the granule cells was observed
at 400 ppm and above (see Table B.6).
Based upon cerebellar damage, the 11-day study (Landry et al., 1983, 1985) identifies a
NOAEL of 50 ppm and a LOAEL of 100 ppm (equivalent to NOAELrec of 94.6 mg/m3 and
LOAELrec of 189.3 mg/m3) for continuous exposure. For intermittent exposure, the NOAEL
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and LOAEL are 150 and 400 ppm (equivalent to NOAELrec of 189.3 and LOAELrec of
378.6 mg/m3), respectively. There was no evidence of damage to spinal or peripheral nerves in
either exposure regimen. The authors noted that these NOAELs were nearly proportionate to the
product of concentration and exposure duration, although the dose-response curve for continuous
exposure was much steeper than that for intermittent exposure. It was also noted that cerebellar
lesions were observed in 150-ppm mice exposed continuously, and these animals also
demonstrated impaired rotating-rod test performance, suggesting a causal relationship. There
was no effect of continuous exposure on rotating-rod test performance at 100 ppm, although all
animals in this group had slight pyknosis and karyorrhexis in the cerebellum.
In a short-term inhalation study reported by Dow Chemical Company (1981),
Sprague-Dawley rats (20/sex/concentration) were exposed to 0, 200, 500, 1000, or 2000 ppm (0,
413, 1033, 2065, or 4130 mg/m3) of chloromethane (purity = 99.5%) for 48 hours, and another
group of 20/sex/concentration were exposed to the same concentrations for 72 hours. Half of the
rats in each group were euthanized at the end of the exposure period, and the remaining animals
were sacrificed after a 12-day recovery period. Histopathology was performed on five
rats/sex/concentration. The LOAEL is 200 ppm (413 mg/m3), based on decreased body weight
in both male and female rats and minimal liver effects in male rats exposed for 72 hours (see
Tables B.7 and B.8). A NOAEL was not established. At >500 ppm, epididymal lesions were
noted that progressed to sperm granulomas. At 1000 and 2000 ppm (HEC equivalent to 1033
and 3065 mg/m3), kidney toxicity predominated, characterized by tubular necrosis and
degeneration, resulting in renal failure.
In another Dow Chemical Company study (McKenna et al., 1981a), three groups of three
male beagle dogs and three male cats (strain not specified) were exposed for approximately
23.5 hours/day, for 3 days (i.e., 72-hour treatment regimen) to chloromethane (purity = 99.5%)
concentrations of 0, 200, or 500 ppm (0, 404, or 1011 mg/m3) with a follow-up period of
26 days. The findings of this study indicate a NOAEL of 200 ppm (404 mg/m3) and a LOAEL
of 500 ppm (1011 mg/m3) based upon a spectrum of neurotoxic findings noted in all three male
dogs exposed to 500 ppm, evident as clinical signs of neurotoxicity (tremors, increased
salivation, limb stiffness, incoordination, loss of balance, weakness, ataxia, and inability to
stand) and microscopic lesions in the spinal cord and brain (vacuolization, swelling and loss of
axons, demyelination and presence of gitter cells).
The histopathology of subacute chloromethane (purity = 99.95%) exposure in one strain
of rat (F344) and three strains of mice (C3H, C57BL/6, B6C3Fi) was investigated by
Morgan et al. (1982). Groups of rats (10/sex/concentration) were exposed 6 hours/day to 0,
2000, 3500, or 5000 ppm (0, 845, 1478, and 2112 mg/m3) for 5 days, then for another 4 days
after a 2-day break (i.e., on Days 1-5 and 8-11). Histopathology was conducted on five
rats/sex/concentration. Groups of mice (five/sex/strain/concentration) were exposed 6 hours/day
to 0, 500, 1000, or 2000 ppm (0, 258, 516, or 1033 mg/m3) for 12 consecutive days. No tabular
data were presented for the control groups. For Selected histopathology F344 rats following
5-days and another 4 days after a 2-days break to chloromethane via inhalation during a 12-days
periods, the LOAEL in rats is 2000 ppm (845 mg/m3), the lowest dose tested, based upon renal,
hepatic, and testicular toxicity, whereas the LOAEL for neurotoxicity is 5000 ppm (2112 mg/m3)
(see Table B.9). In mice, the LOAEL for hepatotoxicity is 500 ppm (258 mg/m3), the lowest
concentration tested (see Table B. 10). However, the dose response was not clearly apparent in
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all the mouse strains/sexes. Cerebellar degeneration, which was most demonstrable in the
female C57BL/6 mouse, supports a LOAEL of 1000 ppm (516 mg/m3), with a NOAEL of
500 ppm (258 mg/m3). This LOAEL is slightly higher than that for the intermittently exposed
female C57BL/6 mice in the study by Landry et al. (1983, 1985), in which the LOAEL is
378.6 mg/m3 (see Table B.6).
Jiang et al. (1985) conducted an ultrastructural study of lesions induced in the cerebella
of C57BL/6 mice (10 females/concentration) exposed 6 hours/day, 5 days/week, for 2 weeks to
0- or 1500-ppm (0 or 553 mg/m3) chloromethane (purity = 99.9%). Under light microscopy, two
types of lesions were found in inner granular layer cells of the cerebellum: (1) a coagulative
necrosis (also seen in controls, but in milder form and in substantially fewer cells) involving
nuclear and cytoplasmic condensation; and (2) a focal malacia involving edema in groups or
extensive areas of cells, with nuclear condensation, karyorrhexis, necrosis, separation of
myelinated axons, and microvacuolation. Electron microscopy confirmed the type-one lesion,
showing pyknotic nuclei without cytoplasmic edema, but with variable disruption of organelles.
Areas of malacia exhibited characteristics, ranging from perikarya edema of granule cells to
near-complete destruction of all tissue components, with the exception of blood vessels (nuclear
pyknosis and condensation, karyorrhexis, organelle remnants). No incidence data were
provided. Few abnormalities were observed in the kidneys of treated females (slight
degeneration of proximal tubules with some proteinaceous material in tubular lumina was seen in
only two animals), leading the study authors to conclude that the reported brain lesions were
probably not a secondary effect of renal toxicity (these types of brain lesions had been associated
with renal insufficiency in humans).
Subchronic-duration Studies
In a 90-day inhalation study for Dow Chemical Company, McKenna et al. (1981b)
exposed groups of CD-I mice (10/sex/concentration), Sprague-Dawley rats
(10/sex/concentration), and male beagle dogs (4/concentration) for 6 hours/day, 5 days/week,
during a 93-95 day period (a total of 64-66 exposures) to chloromethane (purity = 99.9%) at 0,
50, 150, or 400 ppm (0, 18, 54, or 144 mg/m3). Only the results of the statistical analyses (i.e.,
significance) were reported in the data tables for sensory and motor function testing in the study
report; no other quantitative data are available for review. Performance on the wire maneuver
test in female rats at 400 ppm was significantly decreased (p < 0.05) compared to controls during
the second (Days 16-39) and third (Days 40-66) testing intervals. Additionally, during the final
one-third of the study (Days 40-66), performance on the wire maneuver test was decreased
(p < 0.05) in the 150-ppm female rats compared to controls. However, because this finding was
not associated with any discernible neuromuscular incoordination or other deficit, it was
interpreted to be due to general muscular weakness. Additionally, the authors reported a general
decline in performance of this test over time in all groups and postulated that this observation
may be due to increasing body weight. The authors considered the toxicological significance of
this finding to be suspect. The identification of an unequivocal NOAEL/LOAEL for
neurotoxicity from this study is questionable. In the rats, equivocal findings of decreased urine
specific gravity in the 400-ppm males were not corroborated by other findings of nephrotoxicity
(see Table B.l 1). Subtle reversible changes (e.g., altered tinctorial properties) were noted in the
appearance of some hepatocytes from the livers of 5 out of 10 male mice at 400 ppm. However,
similar changes were also observed in some control mice and in 1 out of 7 male mice at
150 ppm. No summary data tables for histopathology were available; only individual pathology
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data were included in the original study report. In conclusion, this study did not reveal any
unequivocal evidence of toxicity related to chloromethane exposure in mice, rats, or dogs, and a
NOAEL of 400 ppm (144 mg/m3) for intermittent subchronic exposure is indicated.
A 90-day inhalation study was also conducted by Battelle for the CUT in F344 rats and
B6C3Fi mice (U.S. EPA, 2001 citing Mitchell et al., 1979a). This study was conducted to select
exposure levels for the 2-year chronic-duration study (detailed subsequently). Animals
(10/sex/species/concentration) were exposed for 6 hours/day, 5 days/week, for 13 weeks to
chloromethane (purity = 99%) at concentrations of 0, 375, 750, or 1500 ppm (0, 138, 277, or
553 mg/m3). Decreased body weight in rats and increased relative liver weight in mice at 750
and 1500 ppm, as well as hepatic histology (cytoplasmic vacuolar change and hepatic infarction)
in mice and rats at 1500 ppm, were considered likely or potentially related to chloromethane
exposure, indicating a LOAEL of 750 ppm (277 mg/m3) and a NOAEL of 375 ppm (138 mg/m3)
(U.S. EPA, 2001). No histopathological effects in the brain in either the mouse or rat were
observed.
Chronic-duration Studies
Battelle conducted a 24-month, chronic-duration inhalation study in F344 rats and
B6C3Fi mice for the CUT (1981). Groups of animals (120/sex/species/concentration) were
exposed 6 hours/day, 5 days/week, for up to 24 months to concentrations of chloromethane
(purity = at least 99%) at 0, 50, 225, or 1000 ppm (0, 18, 83, or 368 mg/m3). Interim sacrifices
and toxicological evaluations were scheduled for 6, 12, and 18 months after initiation of the
study. However, due to high mortality in the 1000-ppm mice, this group was euthanized after 21
or 22 months of exposure. A 6-month interim report of this study was prepared by Mitchell et al.
(1979b). The results of the chronic-duration study were presented in the unpublished final report
by CUT (1981). It was noted that exposures for the 50- and 1000-ppm mice were inadvertently
switched on three consecutive days, so that they received each other's dose; however, the effect
of this exposure mistake was considered negligible by the study authors.
In the CUT study (1981), treatment-related findings in the rats were limited to the
1000-ppm group and were characterized by decreased overall body-weight gain, atrophy and
diffuse degeneration of the seminiferous tubules, and the presence of sperm granulomas. The
following noncancer effects of treatment were observed at 1000 ppm in the mice: decreased
survival; clinical signs of neurotoxicity (hunched posture, tremor, and paralysis); hepatotoxicity
(hepatocellular vacuolization, karyomegaly, cytomegaly, and degeneration and increased ALT);
seminiferous tubule atrophy and degeneration; lymphoid depletion; and atrophy of the spleen.
Additionally in mice in the CUT study (1981), a principal finding was degeneration and atrophy
of the granular layer of the cerebellum. The lesion was found in the 1000-ppm mice that died
spontaneously between 0 and 17 months (15 out of 24 males, 9 out of 20 females) and between
18 and 22 months (45 out of 47 males, 35 out of 37 females). The lesion did not occur at 0, 50,
or 225 ppm. In the 18-24 month spontaneous death category, 35 out of 37 females and 45 out of
47 males in the 1000-ppm group had cerebellar granular cell atrophy that was more extensive at
24 months than at 18 months (U.S. EPA, 2001).
Cancer findings (and findings likely indicating progression to cancer) were limited to the
kidney in males (renal tubuloepithelial hyperplasia, hypertrophy, and/or karyomegaly, and renal
cortical adenomas, adenocarcinomas, papillary cyst/adenocarcinomas). A detailed summary
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table of the number and types of benign and malignant renal lesions (see Table B.12), obtained
from the Concise International Chemical Assessment Document (CICAD) 28, Methyl Chloride
(WHO, 2000), is included in Table B. 12. The following data were obtained from the
Toxicological Review of Methyl Chloride in Support of IRIS (U.S. EPA, 2001):
Cancer findings in the CUT (1981) study were limited to the kidneys in the
1000-ppm male mice. Renal tumors were significantly increased (p < 0.05) in
these animals during Months 12-21; due to early termination, no data from this
group at 24 months was available: 17 renal neoplasms were found in 13 animals
(8 renal cortical adenomas, 4 adenocarcinomas, 2 papillary cystadenomas,
2 tubular cystadenomas, and 1 papillary cystadenocarcinoma). These were
considered induced by chloromethane exposure, as were two adenomas (not
statistically significant) in 225-ppm males at 24 months. A statistically significant
increase in renal cortical cysts was seen at 18-22 months in 7 males and
1 female from the 1000 ppm group, as well as in 1 male and 1 female from the
225 ppm group at 24 months. Also at 24 months, microcysts were observed in
6 males from the 50 ppm group, and 1 control male had a cyst. Although their
precise relationship to each other and to the other renal lesions was not clear,
renal cyst and microcyst formation was considered by the investigators to be
possibly chloromethane-related. However, the low incidence in the 225-ppm
group suggests that it may be a spontaneous lesion. Unpublished data (Johnson,
1988) for controls from eight 2-year mouse studies indicate that the incidence
values for renal microcysts from the CUT (1981) study fall within the Dow
Chemical Company's historical control incidence for this strain. In addition,
examination of nonneoplastic lesions in the B6C3F) from 122 chronic studies
(drinking water, gavage, and inhalation) indicated that in no case was there a
dose-response relationship between chemical exposure and cyst formation. In
fact, control animals in inhalation studies (e.g., butadiene, acetonitrile, toluene)
often evidenced a higher incidence of renal cysts than exposed mice.
Additionally, if one considers the incidence of kidney cysts (no microcysts) in the
NTP chronic inhalation study (TR 385) for methyl bromide (NTP, 1992),
structurally very closely related to chloromethane, there also is no clear
dose-response in male B6C3Fi mice.
Developmental and Reproduction Studies
In a developmental toxicity study, 25 female F344 rats and 33 female B6C3Fi mice were
exposed to 0-, 100-, 500-, or 1500-ppm (0, 52, 258, or 774 mg/m3) chloromethane (purity =
99.98%) for 6 hours/day from Gestation Days (GDs) 7-19 for rats or GDs 6-17 for mice
(Wolkowski-Tyl et al., 1983a). The authors did not provide a LOAEL; however, the following
LOAELs are available from the data. In the rats, the LOAEL for maternal and developmental
toxicity is 1500 ppm (774 mg/m3) based on decreased (p < 0.05) maternal body-weight gain,
body weight, and food consumption and reduced (p < 0.05) fetal body weight and crown-rump
length and a NOAEL of 500 ppm (258 mg/m3). However, there were no treatment-related
external, visceral, or skeletal abnormalities. In the mice, the entire 1500-ppm group was
euthanized in extremis during GDs 10-14, indicating a frank effect level. In all of the dams at
1500 ppm, microscopic examination of the brain revealed selective necrosis of neurons in the
internal granular layer of the cerebellum, ranging from individual cell involvement to focal areas
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comprising large numbers of neurons. The developmental LOAEL for the mice is 500 ppm
(258 mg/m3), based on a small but statistically significant increase in the incidence of heart
defects at this concentration. The anomaly, a reduction or absence of the atrioventricular valve,
chordae tendineae, and papillary muscle, was observed on the left side (bicuspid valve) in three
mouse fetuses (B6C3Fi) and the right (tricuspid valve) in six fetuses. The developmental
NOAEL in mice is 100 ppm (52 mg/m3).
In a further extension of this work, 74-77 female C57BL/6 mice bred to C3H males were
exposed to 0-, 250-, 500-, or 750-ppm (0, 129, 258, or 387 mg/m3) chloromethane (purity =
99.97%) for 6 hours/day, from GDs 6-17 (Wolkowski-Tyl et al., 1983b). At 750 ppm, maternal
toxicity was observed, as evidenced by clinical signs of toxicity (ataxia, hypersensitivity to touch
and/or sound, tremors, and convulsions) and significantly (p < 0.01) decreased body weight and
body weight gain. Six dams died at this concentration, and one was euthanized in extremis,
indicating a frank effect level. The authors did not provide a LOAEL; however, the following
LOAELs are available from the data. The developmental LOAEL is 500 ppm (258 mg/m3)
based on heart malformations found in 7 out of 444 fetuses (1.6%) at 500 ppm, and in 14 out of
400 (3.5%>) fetuses at 750 ppm compared to 2 out of 433 fetuses in the control group. The
developmental NOAEL is 250 ppm (129 mg/m3). This second study confirmed the anomaly in
the tricuspid valve. However, these anomalies were not observed in another laboratory
(John-Greene et al., 1985) in which dams were exposed for 24 hours to 300 ppm (620 mg/m3),
the highest concentration compatible with survival, during the stated critical time interval for
development of these heart structures (GDs 11.5-12.5). Several attempts at replicating the
malformation indicated that its detection may be dependent upon histology preparation and
examination techniques. It was also stated that limited historical control data with this hybrid
strain of mice were available, further complicating its implications for human risk assessment.
In response to the study by John-Greene et al. (1985), one of the original researchers (Tyl, 1985)
conducting the study in which the malformations were found, stated that the attempt to duplicate
these malformations may have failed for two reasons: (1) the exposure time frame (during
GDs 11-12) may have actually preceded the development of the heart structures, and (2) the
exposure duration of 24 hours versus 6 hours/day may have implications on the metabolism of
chloromethane via glutathione. Tyl (1985) recommended repeating the study using the longer
exposure duration in the same strain of mice, in addition to testing rats and rabbits to determine if
heart malformations were observed. Thus, some uncertainty exists regarding the exposure
conditions under which this anomaly occurs, although it is considered prudent to regard
chloromethane as a developmental toxicant in the mouse.
In a two-generation reproduction study, F344 rats (40 males, 80 females) were exposed to
chloromethane (purity = 99.98%>) at concentrations of 0, 150, 475, or 1500 ppm (0, 59, 186, or
589 mg/m3), for 6 hours/day, 5 days/week, for 10 weeks prior to mating (1 male:2 females) and
then for 6 hours/day, 7 days/week, throughout a 2-week mating period (Hamm et al., 1985). At
the end of the mating period, 10 males per group were necropsied, and the females continued
exposure throughout gestation and lactation (except from GD 18 to Postnatal Day 4).
Degeneration and atrophy of the seminiferous tubules were observed in all 1500-ppm F0 males
(10 out of 10), in addition to increased incidences of epididymal sperm granulomas and
decreased testes size in 3 out of 10 animals at this concentration. The remaining 30 males per
group were then removed from exposure and mated during a 2-week period to unexposed
females (1 male:2 females) to determine if decreased fertility was due to effects on the males.
This study identified a reproductive LOAEL at 475 ppm (186 mg/m3) based on statistically
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significant decreased male fertility, with a corresponding NOAEL of 150 ppm (59 mg/m3).
Similar findings were observed whether or not the females were exposed, indicating that reduced
fertility was due to treatment-related effects on the seminiferous tubules and epididymides. The
total number of males proven fertile was significantly (p < 0.05) lower at 475 ppm (17 out of 28)
and 1500 ppm (0 out of 26) compared to controls (25 out of 28). There were no clear effects of
exposure on fertility of the F1 generation (no histopathology was performed). A lower
percentage of male offspring was noted in the 475-ppm F2 litters (41 ± 16%) compared to
controls (51 ± 18%), and a trend toward decreased fertility was observed at 150 ppm (65%) and
475 ppm (61%) compared to controls (78%) in the F1 generation. However, these decreases
were not statistically significant.
Numerous other short-term reproduction toxicity studies have been performed to further
investigate the effects of chloromethane on the epididymides and testes in rats (Chapin et al.,
1984; Working et al. 1985a,b; Working and Bus, 1986; Chellman et al., 1986a,b, 1987; Working
and Chellman, 1989). Table 2 presents a brief summary of the critical effects of these study
summaries; a detailed assessment of these studies is available in the Toxicological Review of
Methyl Chloride: in Support of Summary Information on the Integrated Risk Information System
(U.S. EPA, 2001) and in the Concise International Chemical Assessment Document (CICAD) 28,
Methyl Chloride (WHO, 2000). In general, exposure to chloromethane at concentrations of
1359-3872 mg/m3, for 6 hours/day, for durations of 2-5 days, resulted in unilateral and bilateral
sperm granulomas in the epididymis, decreased fertility (increased preimplantation loss)
determined to be due to increased sperm cytotoxicity (delayed spermiation, chromatin
margination in round spermatids, epithelial vacuolation, luminal exfoliation of spermatogenic
cells, and multinucleated giant cells), decreased sperm motility, and increased incidence of
sperm abnormalities. The postimplantation loss caused by chloromethane in the dominant lethal
assays is considered to be due to inflammation because it was prevented by cotreatment with
3-amino-1-[/??-(trifluoromethyl )phenyl]-2-pyrazoline, the Burroughs Wellcome experimental
compound BW755C, an anti-inflammatory inhibitor of cyclooxygenase and lipoxygenase
enzymes.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
The information included in this section describes the relevant metabolism and
genotoxicity studies that have been reported since the publication of IRIS (U.S. EPA, 2001,
2011). Additionally, a study by Chellman et al. (1986c), which was included in the
Toxicological Review of Methyl Chloride: in Support of Summary Information on the Integrated
Risk Information System (U.S. EPA, 2001), is included to assist in describing the potential
metabolism considerations and their relationship to the toxicity of chloromethane (see Table 3).
The following information regarding the comparative kinetics and metabolism of
chloromethane in humans and animals is obtained from the CICAD 28: Methyl Chloride (WHO,
2000). In rats exposed to 14C-labeled chloromethane by inhalation, the greatest amount of
radioactivity was found in the liver, kidneys, and testes, and, to a smaller extent, in the brain and
lungs. However, the presence of these residues was attributed to the metabolism of
chloromethane to formaldehyde and formate, and their subsequent incorporation into
macromolecules via anabolic pathways. Chloromethane may also bind to macromolecules—
especially protein—and perhaps DNA to a minimal extent. The main route of metabolism of
chloromethane in humans and animals is via conjugation with glutathione. To a lesser extent,
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chloromethane is metabolized via cytochrome P-450 in rat liver, resulting in the formation of
formaldehyde and formate. Formaldehyde and formate may also be formed via the glutathione
pathway. Inhalation of chloromethane by male B6C3Fi mice resulted in a
concentration-dependent depletion of glutathione in the liver, kidney, and brain.
Chloromethane exposure in rats results in time- and concentration-dependent depletions
on tissue (e.g., liver, kidney, testes) levels of nonprotein sulfhydryl (NPSH). The potentially
toxic consequences of NPSH (principally GSH) depletion have not been fully characterized but
may include conversion of chloromethane-GSH conjugates to toxic intermediates (e.g.,
methanethiol and formaldehyde), enhancement of the toxicity of other chemicals that are
normally detoxified by conjugation with GSH, reduction in the capacity of GSH to buffer against
excessive lipid peroxidation, free radical generation, and thiol oxidation; to transport amino
acids; and to serve as a cofactor in enzymatic reactions (e.g., with formaldehyde dehydrogenase)
(U.S. EPA, 2001).
Chellman et al. (1986c) used male B6C3Fi mice to examine the role of GSH (measured
as NPSH) in mitigating the toxicity of chloromethane exposure in brain, liver, and kidney target
tissues. They found that when groups of mice were pretreated with buthionine-S,R-sulfoximine
(BSO), a potent and specific inhibitor of y-glutamylcysteine synthetase—the rate-limiting
enzyme for de novo synthesis of GSH—and then exposed for 6 hours to 2500-ppm
chloromethane (purity = 99%), chloromethane toxicity was prevented. Male mice were also
exposed to 1500-ppm chloromethane (purity = 99%), 6 hours/day, 5 days/week, for 2 weeks, ±
daily pretreatment with BSO. BSO pretreatment protected against both chloromethane-induced
lethality and the induction of lesions in the brain (multiple degenerative/necrotic foci in the
granular cell layer). Hepatic toxicity in male mice exposed for 6 hours to 1500-ppm
chloromethane was reflected in hepatocellular necrosis and cytoplasmic vacuolation, as well as
nearly a 50-fold increase in serum ALT activity. Pretreatment of the animals with 8-mmol BSO,
0.25-mL/kg DEM, or fasting for 18 hours was found to substantially deplete hepatic NPSH and
virtually eliminate hepatotoxicity as measured by serum ALT levels. With respect to kidney
toxicity in animals treated 6 hours/day, 5 days/week, for 2 weeks to 1500-ppm chloromethane,
incorporation of tritiated thymidine into kidney DNA was elevated 3-fold in male mice and
8.5-fold in female mice by the exposure, presumably reflecting compensatory cell regeneration.
In males, pretreatment with BSO completely eliminated this increase, while having no effect on
label incorporation when administered alone (the effect of BSO pretreatment in females was not
determined). This study demonstrates that chloromethane's lethality and target organ toxicity
can largely be prevented by conditions that lower tissue NPSH levels, thus preventing the
formation of chloromethane-GSH conjugates that would result in the metabolic conversion to
toxic intermediates.
In several studies in humans, chloromethane concentrations in breath and blood and
amounts of excreted urinary metabolites have differed greatly among volunteers (WHO, 2000).
One explanation for the large interindividual differences in metabolism and excretion of
chloromethane in humans is the presence or absence of the glutathione-.S'-transferase T1
(GSTT1) gene. The presence of the GSTT1 gene leads to conjugation of chloromethane with
glutathione (GSTT1+), and the absence of this gene results in no conjugation (GSTT1-).
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Lof et al. (2000) demonstrated the toxicokinetics of the GSTT1 polymorphisms in a study
in which 24 volunteers (13 males and 11 females) previously characterized as having high,
medium, or no conjugating activity (8 per group) were exposed to 10-ppm chloromethane
(purity = 97.4%) for 2 hours. The concentrations of chloromethane were measured in inhaled
air, exhaled air, and blood. The experimental data were used in a two-compartment model with
pathways for exhalation and metabolism. Respiratory uptake averages decreased with
decreasing GSTT1 activity. During the first 15 minutes of exposure, the blood concentration of
chloromethane rose rapidly and then plateaued. The blood concentrations of chloromethane
were similar in all three groups during the 2-hour exposure. At the end of the exposure, the
blood concentrations declined rapidly in the high and medium metabolizing groups but declined
more slowly in the group lacking GSTT1 activity. Metabolic clearance was nearly absent in the
nonmetabolizing group. The rate of exhalation clearance was similar among the three groups,
but the nonmetabolizing group had much higher concentrations of chloromethane in exhaled air
after exposure.
Jonsson et al. (2001) subsequently used the data from the GSTT1 -deficient group in the
Lof et al. (2000) study to develop a standard physiologically based pharmacokinetic (PBPK)
model for chloromethane (purity not specified) with six tissue compartments: lung, working
muscle, resting muscle, well-perfused tissues, liver, and fat. The model also included uptake of
chloromethane via inhalation, and all elimination was accounted for by exhalation, because these
individuals lacked the ability to metabolize chloromethane. The PBPK model was fit to the
experimental data in a Bayesian framework using Markov chain Monte Carlo simulation.
Although the model provided good general forecasts, the concentrations in exhaled air and blood
were slightly overpredicted. The authors noted that the use of nonmetabolizing subjects allowed
them to assess the kinetics of a volatile chemical without interference from metabolism and to
obtain greater knowledge of physiological parameters, but using chloromethane as a model
compound had limitations, such as its low solubility in blood, low blood:air partition coefficient,
and rapid decay during the first minutes after exposure.
In a study by Asakura et al. (2008) a gas exposure system using rotating vessels was
improved for exposure of cultured mammalian cells to gaseous compounds in the chromosomal
aberration assay using Chinese hamster lung cells (CHL/IU). This improved system allowed
concurrent testing of three different concentrations, with and without metabolic activation, and
duplicate cultures at each concentration, with positive and negative controls. Chloromethane
(purity = >95%; one of seven chemicals tested) was positive for chromosome aberrations in
cultured Chinese hamster lung cells with and without the presence of microsomal homogenate
(S9) mix.
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Table 3. Other Studies
Tests
Materials and Methods
Results
Conclusions
References
Metabolism
Human
Acute Inhalation
24 human volunteers (13 males/11 females)
with GSTT1 activity characterized as high,
medium, or no conjugating activity (8 per
group) were exposed to 10-ppm
chloromethane for 2 hrs. Chloromethane
(purity = 97.4%) concentrations were
determined in inhaled air, exhaled air, and
blood. The experimental data were used in a
two-compartment model with pathways for
exhalation and metabolism.
Respiratory uptake averages were 243,
158, and 44 |imol for the high, medium,
and no GSTT1 activity groups,
respectively. Metabolic clearance was
high (4.6 L/min) in the high activity group,
intermediate (2.4 L/min) in the medium
conjugating group, and close to zero in the
nonconjugating group. The rate of
exhalation clearance was similar among the
groups.
The authors concluded that GSTT1
appears to be the sole determinant for
chloromethane metabolism in humans.
Lof et al. (2000)
PBPK Modeling
Data from the GSTTl-deficient group in
Lof et al. (2000) were used to develop a
standard PBPK model for chloromethane
(purity not specified) with six
compartments: lung, working muscle,
resting muscle, well-perfused tissues, liver,
and fat. The model also included uptake of
chloromethane via ventilation, and all
elimination was accounted for by exhalation
because these individuals lacked the ability
to metabolize chloromethane.
The model provides a good description of
the concentrations of chloromethane in
arterial blood and exhaled air, although the
final concentrations in exhaled air and
blood were slightly overpredicted.
The use of nonmetabolizing subjects
allowed the authors to assess the
kinetics of a volatile chemical without
interference from metabolism and to
obtain additional knowledge on the
physiological parameters involved.
However, using chloromethane as a
model compound had limitations, such
as low solubility in blood, low blood:air
partition coefficient, and rapid decay
during the first minutes after exposure.
Jonsson et al.
(2001)
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Table 3. Other Studies
Tests
Materials and Methods
Results
Conclusions
References
Acute
Metabolism
Male B6C3Fi mice were pretreated (-1.5 hr
before treatment) with buthionine-S,R-
sulfoximine (BSO), an inhibitor of
glutamylcysteine synthetase (rate-limiting
step in de novo synthesis of GSH) and then
exposed to 2500-ppm chloromethane
(purity = 99.9%) for 6 hr.
Compared to controls (-BSO), GSH in the
+BSO mice at 0, 3, and 6 hr was decreased
in the kidney (to 25, 28, and 32%) and liver
(to 19, 35, and 65%), and in the brain (to
90, 70, and 58%). BSO treatment reduced
mortality at 18 hours from 93% (14/15) to
0% (0/10) and increased the LC50 from
2200 to 3200 ppm.
Chloromethane's lethality and target
organ toxicity can largely be prevented
by conditions that lower tissue NPSH
levels, thus decreasing the formation of
chloromethane-GSH conjugates that
would result in the metabolic
conversion to toxic intermediates.
Chellman et al.
(1986c)
Subacute
Metabolism
Male B6C3Fi mice exposed to 1500-ppm
chloromethane (purity = 99.9%) for 6 hr/d,
5 d/wk, for 2 wk, ± daily pretreatment with
2-mmol BSO.
BSO pretreated animals were protected
against mortality (0% mortality vs.
11-28% in the controls), microscopic
lesions in the brain (multiple
degenerative/necrotic foci in the granular
cell layer), increases in ALT levels, and
incorporation of tritiated thymidine into
kidney DNA.
Genotoxicity
Chinese hamster lung cells were exposed to
chloromethane (purity = >95%) in the
presence and absence of S9 mix using an
improved gas exposure system of rotating
vessels.
Chloromethane was positive for
chromosome aberrations in Chinese
hamster lung cells in the presence and
absence of S9 mix.
Asakura et al.
(2008)
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DERIVATION OF PROVISIONAL VALUES
Tables 4 and 5 below present a summary of noncancer and cancer reference values, respectively.
Table 4. Summary of Noncancer Reference Values for Chloromethane (CASRN 74-87-3)
Toxicity Type (Units)a
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFC
Principal Study
Subchronic p-RfD
(mg/kg-day)
None
Chronic p-RfD
(mg/kg-day)
None
Subchronic p-RfC
(mg/m3)
Mouse/F
Cerebellar lesions
3 x 10°
NOAELrec
94.6
30
Landry et al. (1983, 1985)
Chronic RfC
(mg/m3; IRIS 201 If
Mouse/F
Cerebellar lesions
9 x 10~2
NOAELhec
94.6
1000
Landry et al. (1983, 1985)
"All the reference values obtained from IRIS are indicated with latest review date.
Table 5. Summary of Cancer Reference Values for Chloromethane (CASRN 74-87-3)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
None
p-IUR
None
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DERIVATION OF ORAL REFERENCE DOSES
Chloromethane exists primarily as a gas, and no adequate oral exposure studies are
available. Therefore, no subchronic or chronic p-RfD values can be derived
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
IRIS (U.S. EPA, 2011) provides the following information regarding the rationale for the
selection of the principal study for the derivation of the chronic RfC. This description informs
the selection of the short-term study conducted by Landry et al. (1983, 1985) as the principal
study for the derivation of the subchronic p-RfC.
Dysfunction of the central nervous system (CNS) is a hallmark for toxicity
due to methyl chloride both in human case reports and in short- and long-term
studies in laboratory animals. The 2-year CUT study (1981), which is the only
long-term intermittent (6 hours/day, 5 days/week) inhalation study currently
available, would typically have been chosen for identification of the critical effect
(e.g., cerebellar lesions) because it satisfies the criteria set forth in U.S. EPA
(1994) in spite of several procedural errors (e.g., some misidentification of mice,
pregnancy of some mice, and an exposure error early in the study). However, the
continuous (22-22.5 hr/day) 11-day exposure of the female C57BL/6 mouse
(Landry et al., 1983, 1985) is considered more appropriate in the context of
protecting public health for the following reasons: (1) the study was well
conducted; (2) cerebellar lesions (considered the most critical effect in the
context of known CNS deficits from human case reports) occurred at continuous
exposure levels (100 ppm) and at intermittent levels (400 ppm) far below those in
the B6C3Fi strain exposed chronically (1000 ppm) in the 1981 CUT study; (3) no
cerebellar lesions were observed in the 90-day pilot study in the B6C3F) mouse
(Mitchell et al., 1979[a]) at levels up to 1500ppm; and (4) continuous exposure
of C57BL/6 mice resulted in mortality at 200ppm, whereas intermittent 2-year
exposure of the B6C3F) mouse did not cause mortality below 1000 ppm.
Derivation of Subchronic p-RfC
The study by Landry et al. (1983,1985) is selected as the principal study for
derivation of the subchronic p-RfC. This study, conducted by Dow Chemical Company, was
conducted prior to implementation of Good Laboratory Practice (GLP) standards and was
initially submitted to the EPA under TSCA Section 8(e) (Landry et al., 1983). Subsequently
published in a peer-reviewed journal (Landry et al., 1985), this study meets the standards of
study design and performance, regarding the numbers of animals, examination of potential
toxicity endpoints, and presentation of information. The critical endpoint is cerebellar lesions in
female C57BL/6 mice, with a LOAEL of 189 mg/m3. Cerebellar lesions were observed at higher
concentrations in other short-term studies in dogs and cats (McKenna et al., 1981a) and rats and
mice (Morgan et al., 1982; Jiang et al., 1985); in the chronic-duration toxicity study in mice
(CUT, 1981); and in the developmental toxicity study in mice (Wolkowski-Tyl et al., 1983a). In
addition to being the predominant toxicological endpoint across species, exposure durations, and
concentrations, the cerebellar lesions are considered to be the most relevant toxicological
endpoint because they corroborate the CNS toxicity observed in humans. Although the LOAEL
of 186 mg/m3 in the reproduction study by Hamm et al. (1985), which is based on decreased
male fertility in the F2 generation, is slightly lower than the LOAEL in the study by Landry et al.
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(1983, 1985), there were no clear effects on fertility in the F1 generation. Additionally, CNS
effects were observed across species and across studies as a target organ, the cerebellar lesions in
female C57BL/6 mice (LOAELrec of 189 mg/m3) are the most sensitive endpoint in the most
sensitive species, strain, and sex (Morgan et al., 1982). Therefore, among the available,
acceptable studies, this study provides the lowest POD for deriving a subchronic p-RfC.
Benchmark dose (BMD) analysis is not performed due to the steep dose-response in the observed
cerebellar lesions. The first two exposure levels (28.3 mg/m3and 94.6 mg/m3) showed no effect
for cerebellar lesions but the next four exposure levels showed 100% cerebellar lesions with
different severity, and no statistical analysis was performed. A NOAEL of 50 ppm is selected as
the POD for deriving the subchronic p-RfC.
Adjusted points for daily exposure:
The following dosimetric adjustments were made for each dose in the principal study for
inhalation treatment.
NOAELadj = NOAELLandryetai., 1983,1985 x [conversion from ppm to mg/m3]
[Continuous exposure concentration]
= 50 ppm x (MW -24.45) x (22 hours - 24 hours)
= 50 ppm x (50.49-24.45) x 0.9167
= 94.6 mg/m3
Because the treatment-related effects of chloromethane occur systemically without any
local respiratory effects, the conversion to HEC requires multiplying the adjusted average daily
dose by the animal to human blood:gas partition coefficient (U.S. EPA, 1994). Periodicity is
assumed to be attained for systemic effects, and the blood:gas partition coefficients for humans
(i.e., Nolan et al., 1985) and rats (i.e., Gargas et al., 1989) yield an approximate 1:1 ratio. The
assumption that the partition coefficient for the mouse is similar to that for the rat is based on the
tabulation of Gargas et al. (1989), who reported that blood:gas partition coefficients for six out of
seven chemicals are similar for both the rat and the mouse. Additionally, according to current
modeling practice, a maximum of 1 is used for the animal to human blood:gas partition
coefficient. Thus, using a blood:gas partition coefficient of 1 and the NOAELadj results in an
NOAELrec of 94.6 mg/m3.
NOAELrec = 94.6 mg/m3 x 1 = 94.6 mg/m3
The subchronic p-RfC for chloromethane, based on the NOAELrec of 94.6 mg/m3 in
female mice (Landry et al., 1983, 1985), is derived as follows:
Subchronic p-RfC = NOAELrec ^ UFC
= 94.6 mg/m3 - 30
= 3 x 10° mg/m3 or 3 mg/m3
Tables 6 and 7, respectively, summarize the uncertainty factors (UFs) and the confidence
descriptor for the subchronic p-RfC for chloromethane.
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Table 6. Uncertainty Factors for Subchronic p-RfC of Chloromethane
UF
Value
Justification
ufa
3 (100 5)
A UFa of 3 is applied for animal:human extrapolation to account for the toxicodynamic
portion of the UFA because the toxicokinetic portion (10°5) has been addressed in
dosimetric conversions.
ufd
1
A UFd of 1 is applied because the database has acceptable inhalation developmental
toxicity studies (Wolkowski-Tyl et al., 1983a,b) and a two-generation reproduction
study (Hamm et al., 1985).
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially susceptible
individuals in the absence of definitive information on the variability of response to
humans.
ufl
1
A UFl of 1 is applied because the POD was developed using a NOAEL.
UFS
1
A UFS of 1 is applied because a short-term-duration study with 11-day continuous
exposure is utilized as the principal study to derive a subchronic p-RfC.
UFC <3000
30
Table 7. Confidence Descriptor for Subchronic p-RfC for Chloromethane
Confidence
Categories
Designation3
Discussion
Confidence in Study
H
Confidence in the principal and supporting studies is high.
Confidence in Database
M
Overall confidence in the database is medium because of a lack
of brain histopathology on F1 generation mice, particularly
female C57BL/6, a strain that may be particularly sensitive to
the effects of chloromethane.
Confidence in
Subchronic p-RfCb
M
The overall confidence in the subchronic p-RfC is medium.
"L = Low, M = Medium, H = High.
bThe overall confidence cannot be greater than the lowest entry in table.
Derivation of Chronic RfC
A chronic RfC of 0.09 mg/m3 is available in IRIS (U.S. EPA, 2011), based on cerebellar
lesions in female C57BL/6 mice exposed to 0, 15, 50, 100, 150, 200, or 400 ppm (0, 28.4, 94.6,
189.2, 283.9, 378.5, or 757.1 mg/m3) by whole body inhalation exposure for 11 days for
22 hours per day (Landry et al., 1983, 1985). The IRIS database should be checked to determine
if any changes have been made.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
IRIS (U.S. EPA, 2011) applied the criteria for evaluating the overall weight-of-evidence
(WOE) for carcinogenicity to humans using the Guidelines for Carcinogen Risk Assessment
(U.S. EPA, 1986) and designated chloromethane under the category of Group D, "Not
Classifiable as to its Human CarcinogenicityThe IRIS toxicological review further stated that
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the Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996) suggested that
chloromethane would be classified as an agent for which carcinogenic potential "cannot be
determined." Using the current Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005),
the available data suggest that the cancer WOE descriptor for chloromethane is "Inadequate
Information to Assess Carcinogenic Potential' (see Table 8). This determination is based upon
the evidence available from the studies supporting the IRIS carcinogenicity assessment, in
addition to all relevant studies that have been available since the publication of the IRIS
toxicological review.
Human carcinogenicity data are inadequate. The following information is provided from
IRIS (U.S. EPA, 2001):
The few studies that have examined methyl chloride's potential
carcinogenicity in humans have failed to convincingly demonstrate any
association, and in one instance even indicated a lower cancer incidence than
expected in workers chronically exposed to methyl chloride in a butyl rubber
manufacturing plant (Holmes et al., 1986). There was no conclusive evidence for
an effect of acute, severe exposure to methyl chloride on mortality from all
cancers or from lung cancer in a small cohort accidentally exposed to methyl
chloride from a leaking refrigeration unit (Rafnsson and Gudmundsson, 1997);
because of the wide confidence intervals that included unity, the data cannot be
construed as suggestive of an elevated cancer mortality risk Other occupational
studies involved exposure to multiple chemicals in addition to methyl chloride,
making it difficult to attribute any effects specifically to methyl chloride (Dow
Corning Corporation, 1992b; Olsen etal., 1989).
The epidemiological study by Kernan et al. (1999)—not included in IRIS (U.S. EPA,
2001)—examined death certificates of 63,097 persons who had died from pancreatic cancer in
24 U.S. states from 1984-1993 compared to 252,386 persons who died from causes other than
cancer during the same time period. Results from this study indicate that the deaths from
pancreatic cancer were not associated with exposure to chloromethane.
Animal carcinogenicity data are limited to a single study in which rats and mice were
exposed to 0-, 50-, 225-, or 1000-ppm chloromethane for 6 hours/day, 5 days/week, for up to
2 years (CUT, 1981). The incidences of benign and malignant renal tumors were significantly
increased (p < 0.05) in male B6C3Fi mice at 1000 ppm. Two renal adenomas were noted in the
males at 225 ppm and were considered possibly treatment related. No tumors were found at
lower concentrations or at any other site in the male mouse, nor at any site or concentration in
female mice or F344 rats of either sex. Renal cortical tubuloepithelial hyperplasia and
karyomegaly were also found only in the male mice at 1000 ppm.
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Table 8. Cancer WOE Descriptor for Chloromethane (CASRN 74-87-3)
Possible WOE
Descriptor
Designation
Route of Entry
(Oral, Inhalation, or
Both)
Comments
"Carcinogenic to
Humans "
N/A
N/A
"Likely to be
Carcinogenic to
Humans "
N/A
N/A
"Suggestive Evidence of
Carcinogenic Potential"
N/A
N/A
"Inadequate
Information to Assess
Carcinogenic Potential"
Selected
Inhalation
Under the 2005 Guidelines for Carcinogen Risk
Assessment (U.S. EPA, 2005), it is considered
that there is inadequate information to assess
carcinogenic potential because there is little
pertinent information and/or conflicting
evidence. In animals, only a single 2-year
study (CUT, 1981) was conducted, resulting in
tumors in the kidneys of male mice but no
tumors at any other site or in female mice or
rats of either sex. Human studies were limited
to an epidemiological study in which
pancreatic cancer was not associated with
chloromethane exposure (Kernan et al., 1999),
along with other studies either confounded by
exposure to other chemicals (Dow Corning
Corporation, 1992; Olsen et al., 1989), by
demonstrating a "healthy worker" effect
(Holmes et al., 1986), or by having wide
variability (Rafnsson and Gudmundsson,
1997), thus precluding meaningful
conclusions.
"Not Likely to be
Carcinogenic to
Humans "
N/A
N/A
MODE-OF-ACTION (MOA) DISCUSSION
It has been proposed that the finding of increased incidence of renal tumors in male mice
may be explained by biotransformation of chloromethane to the toxic intermediate,
formaldehyde, via cytochrome P4502E1 (CYP2E1), an androgen-dependent isozyme present in
male mouse kidneys (see IRIS, U.S. EPA, 2011). Concentrations of CYP2E1 are present at
considerably higher concentrations in microsomal preparations from the male mouse kidney
compared to female mice or rats of either sex; however, no CYP2E1 activity was detected in
human kidney microsomal samples. The following discussion of this mechanism of
tumorigenicity in mice and its implications for human carcinogenicity are available from IRIS
(U.S. EPA, 2011):
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The lack of detectable CYP2E1 protein in human kidney (in contrast to
mice, which have high levels) suggests that the metabolism of methyl chloride by
P450 (presumably leading to elevatedformaldehyde concentrations) that could be
responsible for the induction of male mouse kidney tumors may not be relevant to
humans. However, the role of hepatic (and/or kidney) metabolism (leading to
potential genotoxic metabolites) via the predominant GSHpathway (or even by
P450 isozymes other than CYP2E1) in this regard cannot be discounted; in vivo
metabolism of methyl chloride to formate in liver is GSH-dependent, via the
GSH-requiring formaldehyde dehydrogenase that oxidizes formaldehyde to
formate. Inasmuch as methyl chloride exposure can lower tissue nonprotein
sulfhydryl concentrations, it thus has the potential to inhibit formaldehyde
dehydrogenase and increase formaldehyde levels.
Mutagenicity Information
Numerous mutagenicity and other possible mechanistic studies have been reviewed in
support of IRIS, and "these data collectively indicate that methyl chloride is a relatively weak,
direct-acting in vitro genotoxicant at high concentrations, and that its weak DNA-damaging
effects in vivo either are or are likely to be primarily the result of various cytotoxicity-mediated
mechanisms" (U.S. EPA, 2001). This assertion is supported by the studies by Working et al.
(1985a,b), Working and Bus (1986), Chellman et al. (1986a,b, 1987), and Working and
Chellman (1989), which determined that preimplantation losses induced by chloromethane are
due to cytotoxic instead of genotoxic effects (i.e., failure of fertilization), and the
postimplantation loss caused by chloromethane is due to inflammation in the epididymis.
Weak-to-moderate mutagenicity has been demonstrated in Salmonella typhimurium at high
concentrations of chloromethane. Induction of sister chromatid exchanges (SCEs) has been
observed in human lymphoblasts by chloromethane and by a congener, methyl bromide, in
lymphocytes from a human subgroup categorized as "slow metabolizers." This group is known
to be genetically predisposed (polymorphisms in glutathione transferase) to have a lower rate of
metabolism compared with the majority of human populations studied.
Since the evaluation of chloromethane under IRIS (U.S. EPA, 2011), only a single study
was located relevant to the potential genotoxicity of chloromethane (Asakura et al., 2008). A gas
exposure system using rotating vessels was improved for exposure of cultured mammalian cells
to gaseous compounds in the chromosomal aberration assay using CHL/IU. This improved
system allowed concurrent testing of three different concentrations, with and without metabolic
activation, and duplicate cultures at each concentration, with positive and negative controls.
Chloromethane (one of seven chemicals tested) induced structural chromosome aberrations in
cultured Chinese hamster lung cells with and without the presence of S9 mix. Polyploidy was
not observed.
The evidence from the mechanistic, mutagenicity, and genotoxicity studies on
chloromethane indicate that, although it may have mutagenic capability at high concentrations,
any findings observed in vivo are more accurately attributed to cytotoxicity due to inflammation
and not mutagenicity.
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DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
The evaluation of chloromethane for IRIS determined that the human data are inadequate
to judge the carcinogenic potential of methyl chloride and that the findings in the single animal
study on carcinogenicity (CUT, 1981) are equivocal. The lack of data on the carcinogenicity of
chloromethane precludes the derivation of quantitative estimates for either oral (p-OSF) or
inhalation (p-IUR) exposure.
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APPENDIX A. PROVISIONAL SCREENING VALUES
No screening values are presented.
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APPENDIX B. DATA TABLES
Table B.l. Body Weights (g) in Female C57BL/6 Mice Exposed to Chloromethane via
Inhalation Continuously (22 Hours/Day) or Intermittently (5.5 Hours/Day) for 11 Days3
Concentration
(ppm) (HEC, mg/m3)
Day 0
Day 4
Day 8
Day 11
Continuous exposure
0(0)
14.8 ± 1.4
16.1 ± 1.1
16.3 ± 1.3
17.9 ± 1.2b
100 (189.3)
14.9 ± 1.3
15.3 ±1.4 (|5)
15.7 ± 1.1 (44)
16.7 ± 1.1 (47)b
200 (378.6)
15.7 ±2.1
10.7 ± 1.5* (|34)
...
...
400 (757.2)
14.6 ± 1.7
...
...
...
0(0)
16.5 ± 1.2
17.1 ±0.9
17.1 ±0.9
18.1 ±0.9
15 (28.4)
16.1 ± 1.2
16.5 ± 1.6
16.5 ± 1.8
17.8 ± 1.5
50 (94.6)
16.7 ± 1.0
17.0 ±0.8
17.1 ± 1.0
18.2 ± 1.0
150 (283.9)
17.1 ± 1.2
14.4 ± 1.1* (416)
15.0 ± 1.7* (412)
15.9 ± 1.9* (412)
Intermittent exposure
0(0)
15.8 ± 1.8
15.5 ± 1.3
15.3 ± 1.5
16.1 ± 0.7b
400 (189.3)
14.8± 1.1
15.3 ±0.8
14.7 ± 1.2
16.2 ± 0.8b
800 (378.6)
14.8 ± 1.6
14.2 ± 1.8
14.7 ± 1.5
14.9 ± 2.5b
1600 (757.2)
14.7 ± 1.8
14.3 ± 1.6
14.3 ± 1.6
15. ± 0.8b
0(0)
16.2 ± 1.4
17.3 ± 1.4
17.4 ± 1.3
18.2 ± 1.3
150 (71.0)
16.7 ± 1.4
17.3 ± 1.5
17.3 ± 1.5
17.8 ± 1.4
2400 (1135.8)
17.0 ± 1.2
15.9 ± 1.1* (48)
14.6 ± 1.2* (416)
—
aLandry et al. (1983, 1985). Data (mean ± SD) were obtained from Table 2 on page 91; n = 12, except as noted.
hn = 6 (only mice that underwent gross pathology were weighed).
* Statistically different from the controls at p< 0.05.
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Table B.2. Rotating-rod Test Performance of Female C57BL/6 Mice Exposed to
Chloromethane via Inhalation Continuously (22 Hours/Day) or Intermittently
(5.5 Hours/Day) for 11 Days"
Concentration
(ppm) (HEC, mg/m3)
Terminal Rod Speed (rpm)
Day 4
Day 8
Day 11
Continuous exposure
0(0)
37 ±7
34 ±5
36 ±5
100 (189.3)
36 ±5
36 ±7
33 ±5
200 (378.6)
0.0b
C
—
400 (757.2)
C
—
—
0(0)
41 ± 8
46 ± 12
39± 11
15 (28.4)
45 ±9
49± 11
51 ± 12
50 (94.6)
39 ± 10
50 ± 14
51 ± 10
150 (283.9)
17 ± 10 (|59)
12 ±9* (474)
C
Intermittent exposure
0(0)
34 ±6
36 ±6
35 ±7
400 (189.3)
30 ±4
39 ±9
37 ±3
800 (378.6)
29 ±4* (|15)
36 ±7
34 ±6
1600 (757.2)
26 ±4* (415)
36 ±7
33± 11
0(0)
42 ±7
45 ± 7d
40 ±8
150 (71.0)
38 ±6
40 ± 10
46 ±7
2400 (1135.8)
27 ±6* (436)
7± 15*b(484)
—
aLandry et al. (1983, 1985). Data (mean ± SD) were obtained from Table 4 on page 93; n = 10-12, except as noted.
In cases when a mouse would repeatedly jump off the rod, the value was excluded from analysis.
bMoribund mice were scored as 0 rpm. Several mice were not considered moribund but scored zero on the test.
°Moribund or dead.
dn = 9.
* Statistically different from the controls at p< 0.05.
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Table B.3. Terminal Absolute and Relative Organ Weights of Female C57BL/6 Mice
Exposed to Chloromethane via Inhalation Continuously (22 Hours/Day) or Intermittently
(5.5 Hours/Day) for 11 Daysa
Concentration
(ppm)
(HEC, mg/m3)
Liver
Kidney
Thymus
g
g/lOOg
g
g/ioo g
g
g/lOOg
Continuous exposure
0(0)
1.03 ±0.13
5.73 ± 0.46
...
—
0.073 ±0.014
0.410 ±0.072
100 (189.3)
0.93 ±0.15
5.57 ±0.71
...
—
0.072 ±0.010
0.434 ±0.049
0(0)
0.99 ±0.08
5.43 ±0.30
0.23 ±0.01
1.29 ±0.06
0.070 ±0.010
0.386 ±0.050
15 (28.4)
0.95 ±0.07
5.34 ±0.32
0.23 ± 0.02
1.31 ±0.06
0.054 ±0.018*
(423)
0.303 ±0.085*
(422)
50 (94.6)
1.01 ±0.08
5.57 ±0.38
0.23 ± 0.02
1.26 ±0.08
0.055 ±0.015*
(421)
0.306 ±
0.084*(|21)
150 (283.9)
0.86 ±0.13*
(413)
5.43 ±0.32
0.22 ± 0.02
1.40 ±0.10*
(T9)
0.020 ±0.011*
(471)
0.120 ±0.057*
(469)
Intermittent exposure
0(0)
0.80 ±0.07
5.00 ±0.36
...
—
0.068 ±0.011
0.422 ± 0.048
400 (189.3)
0.80 ±0.06
4.95 ±0.34
...
—
0.061 ±0.019
0.378 ±0.117
800 (378.6)
0.80 ±0.13
5.36 ±0.20
...
...
0.065 ±0.018
0.432 ±0.073
1600 (757.2)
0.98 ±0.06*
(T23)
6.14 ±0.28*
(T23)
...
...
0.041 ±0.007*
(440)
0.258 ±0.041*
(439)
0(0)
0.96 ±0.10
5.29 ±0.37
0.23 ± 0.02
1.34 ±0.10
0.072 ±0.012
0.397 ±0.062
150 (71.0)
0.96 ±0.12
5.38 ±0.47
0.24 ± 0.02
1.30 ±0.05
0.068 ± 0.020
0.381 ±0.114
2400 (1135.8)
0.88 ±0.20
5.76 ±0.88
0.23 ± 0.02
1.60 ±0.07
(t 19)
0.008 ±0.003*
(489)
0.051 ±0.021*
(487)
"Landry et al. (1983, 1985). Data (mean ± SD) were obtained from Table 3 on page 92; n = 12, except as noted.
Kidneys were not weighed at the termination of the first exposure series.
* Statistically different from the controls at p £ 0.05.
44
Chloromethane
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Table B.4. Principal Microscopic Findings in Female C57BL/6 Mice Exposed to
Chloromethane via Inhalation Continuously for 11 Days3
Lesion
Exposure Group (ppm) (HEC, mg/m3)
0(0)
15 (28.4)
50 (94.6)
100
(189.3)
150
(283.9)
200
(378.6)
400
(757.2)
Number examined
28
12
12
6
12
12
22
Pyknosis/karyorrhexis of granule cells in the cerebellum
Slight
0
0
0
6
0
0
2
Moderate
0
0
0
0
12
0
4
Severe
0
0
0
0
0
12
16
Total
0(0)b
0(0)
0(0)
6 (100)
12 (100)
12 (100)
22 (100)
Decreased size of hepatocytes due to decreased glycogen
Slight
1
0
0
0
1
0
0
Moderate
0
0
0
1
1
1
7
Severe
0
0
0
1
7
11
14
Total
1(4)
0(0)
0(0)
2 (33)
9(75)
12 (100)
21 (95)
Hepatocyte degeneration or
necrosis
0
0
0
0
0
1(8)
18 (82)
aData were obtained from Table 2 on page 30 of the Toxicological Review (U.S. EPA, 2001), referencing
Landry et al. (1983, 1985).
dumber (percent) affected.
45
Chloromethane
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12-4-2012
Table B.5. Duration Dependence of Principal Microscopic Findings in the 150-ppm Female
C57BL/6 Mice Exposed to Chloromethane via Inhalation Continuously for 11 Days3
ppm (HEC,
mg/m3)
Day 1
Day 2
Day 4
Day 6
Day 8
Day 11
Number necropsied
0(0)
5
5
5
5
5
12
150 (283.9)
5
5
5
5
5
12
Cerebellum
Vacuolation of white
matter (slight)
0(0)
0
0
0
0
0
0
150 (283.9)
0
0
0
1
0
12 (100)
Increased
pyknosis/karyorrhexis of
granule cells (multifocal)
0(0)
0
0
0
0
0
0
150 (283.9)
0
0
5 (100)b
2(40)
5 (100)
12 (100)
Loss of cells in granule
layer with focal severe
areas containing
macrophages
0(0)
0
0
0
0
0
0
150 (283.9)
0
0
0
0
4 (80)
12 (100)
aData were obtained from Table 4 on page 47 of the Toxicological Review (U.S. EPA, 2001), referencing Landry et al. (1983,
1985).
'Number (percent) affected.
Table B.6. Principal Microscopic Findings in Female C57BL/6 Mice Exposed to
Chloromethane via Inhalation Intermittently for 11 Days3
Lesion
Exposure Group (ppm) (HEC, mg/m3)
0(0)
150 (71.0)
400 (189.3)
800 (378.6)
1600 (757.2)
2400
(1135.8)
Number examined
28
12
6
6
17
12
Increased pyknosis and karyorrhexis of granule cells
Slight
0
0
2(33)
4(67)
11 (65)
12 (100)
Decreased size of hepatocytes due to decreased glycogen
Slight
8
0
1
0
0
0
Moderate
2
0
2
0
4
2
Severe
0
0
0
3
0
3
Total
10 (36)b
0
3(50)
3(50)
4 (24)
5(42)
"Data were obtained from Table 5 on page 48 of the Toxicological Review (U.S. EPA, 2001), referencing
Landry et al. (1983, 1985).
dumber (percent) affected.
46
Chloromethane
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12-4-2012
Table B.7. Body Weights (g) of Sprague-Dawley Rats Exposed to Chloromethane via
Inhalation for 72 Hours Followed by 12 Days of Recovery"
Postexposure Day
Concentration (ppm) (HEC, mg/m3)
0(0)b
200 (413)
500 (1033)
0b
1000 (2065)
2000 (4130)
Males
0
295 ± 11
282 ± 9*
251±12*
214 ±9
149 ±9*
...
1
296 ± 13
...
267 ± 9*
...
...
...
4 [3]°
319± 13
312± 11
300±10*
235 ± 10
128 ± 27*
...
6 [5]°
327 ± 10
329 ± 12
307±12*
251 ± 12
145 ±43*
...
7 [7]c
338 ± 12
341 ± 15
323±12*
270 ± 10
190 ± 20*
...
11 [10]°
351 ± 14
351 ± 18
336 ± 14
292 ± 12
218 ±27*
...
Females
0
180 ±8
159 ±20*
163 ± 12*
175 ± 10
125 ±7*
...
1
180 ±9
...
172 ± 11
...
...
...
4 [3]°
193 ±8
180± 10*
188 ± 10
180 ± 12
127 ± 26*
...
6 [5]°
198 ±9
185± 15*
192 ± 12
189 ± 10
139 ±44*
...
7 [7]c
205 ± 10
196 ± 10
199 ± 11
195 ± 11
179 ±2*
...
11 [10]°
209 ± 10
197 ± 16
203 ± 14
204 ± 1
190 ±5
...
aDow Chemical Company (1981). Data (mean ± SD) were obtained from Table 3 on page 37 and Table 5 on page
39: n = 10, except for the 1000-ppm group, where n = 4-6 in the males and 2-3 in the females beginning on
Postexposure Day 3. Percent differences from controls are included in parentheses.
bThe study was divided into two exposure groups, one group in which animals were exposed to 0, 200, and 500 ppm
and the other in which rats were exposed to 0, 1000, and 2000 ppm. Therefore, the concurrent control group is
presented with each concentration.
°Exposure for the 200-ppm group began 1 day later than the remaining groups; therefore, body weights of the
200-ppm animals were not reported for Day 1 postexposure, and the subsequent measurements for this group
occurred 1 day earlier (actual day included in brackets).
* Statistically different from the controls at p< 0.05.
47
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Table B.8. Selected Histopathological Findings in F344 Rats Following 72 Hours of
Exposure to Chloromethane via Inhalation"
Concentration (ppm) (HEC, mg/m3)
0(0)b
200
500
0(0)b
1000
2000
Microscopic Lesion
(413)
(1033)
(2065)
(4130)
Males
Altered tinctorial properties of the hepatocytes
0
4
3
0
2
4
Females
Altered tinctorial properties of the hepatocytes
0
0
0
0
5
2
aDow Chemical Company (1981). Data (number affected) were obtained from Tables 20, 33, and 44 on pages 60,
79, and 94, respectively; n = 5.
bThe study was divided into two exposure groups, one group in which animals were exposed to 0, 200, and 500 ppm
and the other in which rats were exposed to 0, 1000, and 2000 ppm. Therefore, the concurrent control group is
presented with each concentration.
Table B.9. Selected Histopathology in F344 Rats Following 9 Days of Exposure to
Chloromethane via Inhalation During a 11-Day Period3
Microscopic Lesion
Concentration (ppm) (HEC, mg/m3)
2000 (845)
3500 (1478)
5000 (2112)
Males
Kidney—degeneration and necrosis of renal proximal
convoluted tubules
8
10
10
Liver—hepatocellular degeneration
0
9
10
Testes—degeneration
10
10
10
Cerebellum—degeneration
0
0
3
Females
Kidney—degeneration and necrosis of renal proximal
convoluted tubules
0
5
10
Liver—hepatocellular degeneration
8
9
9
Cerebellum—degeneration
0
0
2
"Morgan et al. (1982). Data (number affected) were obtained from Table 1 on page 294; n = 10. Data for control
groups were not presented.
48
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Table B.10. Selected Histopathology in Mice Following 12 Days of Exposure to
Chloromethane via Inhalation3
Microscopic Lesion
Strain of Mouse
Concentration (ppm) (HEC, mg/m3)
500 (258)
1000 (516)
2000 (1033)
Males
Liver—hepatocellular degeneration
C3H
2/5
0/4
4/5
C57BL/6
3/5
3/5
5/5
B6C3Fi
0/5
0/5
5/5
Cerebellum—degeneration
C3H
0/5
0/4
0/5
C57BL/6
0/5
3/5
0/5
B6C3FJ
0/5
0/5
0/5
Females
Liver—hepatocellular degeneration
C3H
0/5
0/5
0/5
C57BL/6
2/5
3/5
0/5
B6C3Fi
0/5
0/5
4/5
Cerebellum—degeneration
C3H
0/5
0/5
0/5
C57BL/6
0/5
5/5
4/4
B6C3FJ
0/5
0/5
2/5
aMorgan et al. (1982). Data (number affected/number examined) were obtained from Table 1 on page 294. Data for
control groups were not presented.
Table B.ll. Specific Gravity Values for Rats Following 90 Days of Exposure to
Chloromethane via Inhalation3
Concentration (ppm)
Time
0
50
150
400
Males
Preexposure
1.045 ±0.013
1.045 ±0.007
1.042 ±0.009
1.045 ±0.007
Preterminal
1.043 ±0.009
1.038 ±0.010
1.036 ±0.007
1.029 ±0.010
Females
Preexposure
1.037 ±0.009
1.033 ±0.011
1.031 ±0.009
1.036 ±0.010
Preterminal
1.027 ±0.007
1.026 ±0.008
1.017 ±0.009
1.023 ±0.006
"McKcnna et al. (1981b). Data were obtained from Table 7 on page 33\n = 10.
49
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12-4-2012
Table B.12. Incidences of Lesions in Renal Cortex of Male B6C3Fi Mice Exposed to
Chloromethane via Inhalation for 24 Months3
Lesion
Exposure Group (ppm)
0
50
225
1000
Adenocarcinoma
0/120 (0)b
0/118(0)
0/117(0)
5/120 (4.2)
Papillary cyst, adenocarcinomas
0/120 (0)
0/118(0)
0/117(0)
1/120 (0.8)
Adenoma
0/120 (0)
0/118(0)
2/117 (1.7)
12/120 (10)
Papillary cyst, adenomas
0/120 (0)
0/118(0)
0/117(0)
2/120 (1.7)
Tubuloepithelium hypertrophy,
hyperplasia, and/or karyomegaly
0/120 (0)
0/118(0)
0/117(0)
44/120 (36.7)
aData were obtained from Table 3 on page 17 of Concise International Chemical Assessment Document (CICAD)
28, Methyl Chloride (WHO, 2000), citing CUT (1981).
dumber affected/number examined (percent affected).
50
Chloromethane
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12-4-2012
APPENDIX C. BMD MODELING OUTPUTS FOR CHLOROMETHANE
There are no BMD modeling outputs for chloromethane.
51
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