EPA
United States
Environmental Protection Agency
Office of Chemical Safety and
Pollution Prevention
Final Risk Evaluation for
Methylene Chloride
Systematic Review Supplemental File:
Data Extraction Tables for Human Health Hazard Studies
CASRN: 75-09-2
H
June 2020
-------
Table of Contents
1 DATA EXTRACTION TABLE FOR EPIDEMIOLOGY STUDIES 4
2 DATA EXTRACTION TABLES FOR NON-CANCER ENDPOINTS FROM
ANIMAL TOXICITY STUDIES 21
2.1 Acute and Short-term Animal Toxicity Studies 21
2.2 Subchronic and Chronic Animal Toxicity Studies 25
2.3 Reproductive and Developmental Outcomes from Animal Toxicity Studies 32
3 DATA EXTRACTION TABLES FOR ANIMAL CANCER BIOASSAYS 34
3.1 Liver Tumor Data from Cancer Bioassays 34
3.2 Lung Tumor Data From Animal Cancer Bioassays 36
3.3 Mammary Gland Tumors from Animal Cancer Bioassays 37
3.1 Other Tumor Data From Animal Cancer Bioassays 39
4 4 DATA EXTRACTION TABLES FOR GENOTOXICITY STUDIES 41
4.1 Methylene Chloride Genotoxicity Studies not Cited in the 2011 IRIS Assessment. 41
4.2 Results from in vitro Genotoxicity Assays of Dichloromethane in Nonmammalian
Systems 43
4.3 Results from in vitro Genotoxicity Assays of Dichlorom ethane with Mammalian
Systems by Test Type 45
4.4 Results from in vivo Genotoxicity Assays of Dichloromethane in Insects 48
4.5 Results from in vivo Genotoxicity Assays of Dichloromethane in Mice 49
4.6 Results from in vivo Genotoxicity Assays of Dichloromethane in Rats and Hamsters
51
5 REFERENCES 52
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NOTE: Within each table, rows that are shaded are the new studies identified in the updated
literature search or newly identified. Some of these studies were submitted under TSCA (e.g.,
section 8e, 8d, etc) or published in journal articles several years ago and thus have older dates.
Rows that are not shaded are the key and supporting studies from the IRIS Assessment (U.S.
EP V 2011). Studies that received unacceptable data quality ratings are not included in the
tables below.
3
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1 Data Extraction Table for Epidemiology Studies
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Cancer
Non-Hodgkin lymphoma
(NHL)
518 women diagnosed with
NHL between 1996 and 2000
and 597 control women
Job exposure matrix
(ever/never exposed to
methylene chloride)
The risk of NHL was
increased with exposure to
methylene chloride; OR
(95% CI) = 1.69(1.06,
2.69). For the diffuse large
B-cell lymphoma subtype,
the risk was also
significantly increased
with exposure to
methylene chloride; OR
(95% CI)-2.10 (1.15,
3.85).
Barrv et al
(2
High
Cancer
Breast cancer mortality
132,352 white women and
18,591 black women across
24 US states, 14.2 percent
and 24.7 percent of cases
were under 50 for white and
black women, respectively.
50 percent of black cases
and 30 percent of white
cases were considered
exposed to methylene
chloride.
Breast cancer mortality
risk was significantly
elevated for white and
black women in the highest
level of exposure. Risk of
breast cancer mortality was
significantly reduced in the
first level of exposure for
white women.
Cantor et al.
(1995)
High
4
-------
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Cancer
Diagnosis of cancer in oral
cavity, oropharynx,
hvpopharvnx. oral cavity, and
larynx (detailed list of codes in
text)
Case-control, women only.
296 cases. 775 controls,
diagnosed 2001-2007. general
population. 18-85 years,
subset of ICARE cohort
Methylene chloride exposure
qualitatively slated as ever
(job with likely exposure
> 1 month) or never
Non-significant positive
association between
methylene chloride and
head/neck cancers in
ever/never and continuous
cumulative exposure
analysis: non-significant
negative association for
those exposed exclusively
to methylene chloride
(limited sample size)
Medium
Cancer
Cancers of the bladder,
prostate, colon, stomach,
rectum, kidney, esophagus,
liver, and pancreas, as well as
melanoma and non-Hodgkin's
lymphoma
3730 male. Canadian patients
aged 35 to 70 years diagnosed
1979-1985 in 18 largest
Montreal hospitals: 533
controls from electoral lists
in Quebec. A second control
group consisted of the
population controls together
with patients with cancers at
sites distal to the primary
cancer being assessed.
Methylene chloride exposure
determined from self-
reported job history
categorized by chemists and
industrial hygienists based
on degree of confidence,
frequency, and relative
levels (not quantitative)
Non-significant OR for all
cancer types
Medium
Cancer
Meningioma mortality
(1984-1992), United States,
649000 women (12980 cases,
51920 controls)
Methylene chloride exposure
based on a job exposure
matrix and occupation code
Methylene chloride was
not significantly associated
with risk of meningioma
mortality.
Cocco et al,
(1999)
Medium
Cancer
Leukemia and chronic
lymphatic leukemia
355 cases of leukemia and
811 controls, and 103 cases
of chronic lymphatic
leukemia and 925 controls in
Italy, ages 20 to 74
Methylene chloride exposure
based on employment
questionnaire and expert
rating
A significant association
between exposure to
methylene chloride and
leukemia and chronic
lymphatic leukemia was
not observed at either
exposure level
Costantini et al,
(2008)
Medium
5
-------
T.iifyM Origin/
Sj Mom
Ouloomo/ liidpninl
Slmlj Popiihilion
l'l\|)OMII'0
Komi lis
Roforonoo
Diilii Qu;ilil\
l-'.\ iiliiiilion
Cancer
Renal cell carcinoma
White newly diagnosed cases
with age- and gender-
stratified random sample
white controls
JEM (developed by NCI)
No significant association
between methylene
chloride and RCC for the
total population nor when
separated by sex
Dosemeci et al,
(1999)
Medium
Cancer
Breast cancer incidence
Participants in the California
Teacher Study. 1995-2011.
(n=l 12.378 women)
National-Scale Air Toxics
Assessment modeled air
coiiccnl.ral.ions
No significant association
between breast cancer
incidence and methylene
chloride exposure
High
Cancer
Cause-specific mortality to
liver cancer, prostate cancer,
pancreatic cancer, and cervical
cancer
2187 men and 1024 women
working in Amcelle plant in
Cumberland, Maryland,
1970-1981
38.2 and 14.3 percent of men
and women exposed at the
high methylene chloride
exposure level (350 to 700
ppm), respectively
Prostate and cervical
cancer mortality were
elevated in both high and
low exposure groups, but
not significant. No
significant association
observed between
exposure to methylene
chloride and liver or
pancreatic cancer in both
men and women
Gibbs et al,
(1996)
High
6
-------
T.iifyM Origin/
Sj Mom
Ouloomo/ l.ndpninl
Slmlj Population
l'l\|)OMIIV
Komi lis
Roforonoo
Diilii Qu;ili(.\
l-'.\ iiliiiilion
Cancer
Multiple myeloma
180 cases of multiple
myeloma (diagnosed between
January 1, 2000 and March
21, 2002; 35-74 years old)
and 481 controls (35-74 years
old)
Exposure to methylene
chloride estimated with job
exposure matrix. Individual
cumulative exposure scores
were calculated by
multiplying the midpoint of
the intensity (in ppm) by the
midpoint of the frequency
(in hours/week) by the
number of years worked in
each exposed job.
When individuals with
reported exposure rated as
"low confidence" were
considered unexposed, a
significantly increased risk
of multiple myeloma was
observed in individuals
ever exposed to methylene
chloride; OR (95% CI) =
2.0 (1.2 to 3.2). A
significant exposure-
related trend (p < 0.05)
was also observed for
duration of exposure. A
near-significant exposure-
related trend (p=0.06) was
observed for cumulative
exposure score with a 10-
year lag.
Gold et al,
(2010)
High
Cancer
Liver and biliary cancer
Male employees in
photographic film support
manufacturing (n=l,311),
Eastman Kodak Company,
Rochester, NY, 1946-1970
Methylene chloride, area and
personal air samples
Occupational exposure to
methylene chloride was
not significantly associated
with death from liver or
biliary cancer.
Heame and
Pifer f 1999)
High
Cancer
Astrocytic brain cancer risk
Men in southern Louisiana,
United States, exposed from
1978 - 1980; in northern New
Jersey and Philadelphia,
Pennsylvania, United States,
exposed from 1979 - 1981
(n=620, 300 cases, 320
controls)
Methylene chloride, medium
exposure (2)
Chi trend for methylene
chloride= 2.08; Exposure
significantly associated
with astrocytic brain
cancer
Heineman et al,
(1994)
Medium
7
-------
T.iifyM Origin/
Sj Mom
Ouloomo/ l.ndpninl
Slmlj Population
l'l\|)OMIIV
Komi lis
Roforonoo
Diilii Qu;ili(.\
l-'.\ iiliiiilion
Cancer
Prostate cancer mortality
Employees of a cellulose
acetate/triacetate fibers plant
(n=3211;2187 men, 1024
women), Cumberland, MD,
1970-1989
Methylene chloride, area and
personal air samples taken at
a similar plant owned by the
same company
High occupational
exposure to methylene
chloride was significantly
positively associated with
death from prostate cancer
in men with more than 20
years since first exposure.
There was also evidence of
a non-significant, positive
dose-response relationship
between methylene
chloride exposure and
prostate cancer mortality.
Gibbs (1992)
Medium
Cancer
Childhood acute lymphoblastic
leukemia
790 mothers interviewed
from both case and control
groups in Quebec Canada
between 1980 and 2000;
Children 0-14 yrs old. 848
cases, 916 controls
Methylene chloride exposure
to mothers 2 years before
pregnancy, and up to birth;
Exposure level 0 (baseline),
no exposure
(none or possible); level 1,
some exposure (exposure
resulting in concentration x
frequency < 4), and level 2,
greater exposure
(concentration x
frequency > 4)
Maternal exposure to
methylene chloride before
or during pregnancy
resulted in increased, but
non-significant risk of
acute lymphoblastic
leukemia in children
Infante-Rivard
et al, (2005)
High
Cancer
Cholangiocarcinoma
95 proof-printing workers.
Osaka. Japan. 1987-2006
Methylene chloride, mean
cumulative exposure (ppm-
ycars). 591
Significant increase in
cholangiocarcinoma
incidence in this sample
compared to the general
population of Japan.
Incidence rate ratios arc
not significant.
Medium
8
-------
T.iifyM Origin/
Sj Mom
Ouloomo/ l.ndpninl
Slmlj Population
l'l\|)OMIIV
Komi lis
Roforonoo
Diilii Qu;ili(.\
l-'.\ iiliiiilion
Cancer
Cause-specific mortality
1271 textile workers, Rock
Hill, South Carolina, 1954-
1986
Methylene chloride, 8-hour
TWA (ppm) 1700
Significant excess
mortality for cancer of the
biliary passages & liver; all
other cancer SMRs non-
significant
Lanes et al,
(1990)
Medium
Cancer
Mortality from malignant
neoplasms (total; buccal cavity;
biliary passages and liver;
melanoma; bronchus, trachea
and lung; breast; pancreas)
Cellulose fiber production
workers (n=1271, Rock Hill,
South Carolina)
Methylene chloride in 1977
median of 140, 280, and 475
ppm in three main areas
Methylene chloride was
not significantly associated
with any mortality;
however, SMRs were
elevated for biliary
passages and liver
malignant neoplasms and
melanoma.
Lanes et al,
f]9931
Medium
Cancer
Lung cancer
Investigation of occupational
and environmental causes or
respiratory cancers (ICARE)
part icipants population-based
case-control study in France
200.1-2007 (2274 men cases
and 2780 men controls)
Cumulative Exposure Index
(CEI) based on self-reported
job histories and probability,
intensity, and frequency of
exposure to methylene
chloride based on jobs
Methylene chloride was
not significantly associated
with lung cancer in men.
Medium
Cancer
All Non-Hodgkin lympma and
by Non-Hodgkin lymphoma
subtype (i.e,. small
lymphocytic, follicular, diffuse,
other),
All newly diagnosed cases of
Non-Hodgkin lymphomas,
chronic lymphocytic
leukemia (CLL) during
1991a€"1993 among men and
women age 20 to 74 years in
11 areas in Italy
Methylene chloride exposure
based on job-specific
questionnaires and industrial
hygiene experts for level of
probability (i.e,. low,
medium, high) and intensity
of exposure (i.e., very low,
low, medium, and high) with
durations of less than 15
years and 15 or more years.
Methylene chloride was
not significantly associated
with non-Hodgkin
lymphoma either based on
intensity or duration of
exposure; however, there
was an increase in the risk
for small lymphocytic non-
Hodgkin lymphoma
(borderline significance)
with medium/high
intensity.
Miliei et al,
(2006)
High
9
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Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Cancer
Mycosis fungoides (MF)
100 patients with Mycosis
Fungoides and 2846 controls.
35-69 years of age. from
Denmark. Sweden. France.
Germany. Italy, and Spain.
1995-1997
Occupational exposure to
methylene chloride assessed
with job exposure matrix
A negative, non-significant
association was observed
between Mycosis
Fungoides and subjects
with exposure to
methylene chloride >=
median of control exposure
vs. unexposed subjects
High
Cancer
Brain cancer: glioma and
meningioma cases
489 glioma cases. 197
meningioma cases, and 799
controls from three USA
hospitals in Arizona.
Massachusetts and
Pennsylvania
Occupational exposure to
methylene chloride via self-
reported occupational history
and industrial hygicnisl
assigned level of exposure
Methylene chloride was
not associated with glioma
or meningioma
High
Cancer
Diagnosis of kidney cancer
General population case-
control study of kidney
cancer (1217 cases: 1235
controls). Detroit (2002 -
2007) and Chicago (2003).
Job exposure matrix was
used to determine years
exposed, average weekly
exposure and cumulative
hours exposed to methylene
chloride.
No significant associations
observed between
exposure to methylene
chloride and kidney cancer
High
Cancer
Mortality from breast cancer
Aircraft maintenance workers
(n = 14,457; 10,730 men and
3725 women) at Hill Air
Force Base (Utah, USA), for
at least one year from 1952-
1956, and followed up
through 2000
Occupational exposure to
methylene chloride (yes/no)
based on job-exposure
matrix; no quantitative
assessment available
Positive, non-statistically
significant association
between breast cancer
mortality in females and
occupational exposure to
methylene chloride
compared to no exposure
Radical! et al,
(2008)
Medium
10
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Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Cancer
Glioma
Non-farm workers from the
Upper Midwest Health Study
(798 cases and 1141 controls
from Iowa. Michigan.
Minnesota, and Wisconsin
1995-1997)
Methylene chloride use
(self-reported occupational
history through 1992.
bibliographic database of
published exposure)
Methylene chloride was
associated with a
significant decrease in
gliomas only when
i ncluding proxy -only
interviews and unexposed
participants or as
ever/never exposure.
High
Cancer
Total lymphoma, HL, B-NHL,
T-NHL, B-NHL subentities
(DLBCL, FL, CLL, multiple
myeloma, marginal zone
lymphoma)
710 participating cases
(matched to 710 controls)
with malignant lymphoma
among men and women aged
18 to 80 years in 6 regions in
Germany
Cumulative occupational
exposure to methylene
chloride [ppm*years] based
on intensity, the frequency,
and duration of methylene
chloride exposure (0, >0 to
<26.3, >26.3 to <=175, >175
ppm*years)
Methylene chloride was
not significantly associated
with malignant lymphoma;
however, exposure to >175
ppm*yrs was associated
with an increased (non-
significant) risk of
malignant lymphoma, B-
cell non-Hodgkin's
lymphoma and T-cell non-
Hodgkin's lymphoma.
Seidler et al,
(2007)
High
Cancer
Rectal cancer incidence
Greater Montreal
metropolitan area. Case-
control study of
occupationallv-exposed men
aged 35 to 70 year old (4263
cases. 533 population
controls: also hospital and
cancer controls).
Any or substantial exposure
The ORs for any and
substantial exposure to
methylene chloride
exposure and rectal cancer
were significantly elevated
at the p=0.1 level (one-
sided).
Medium
Cancer
Brain and other nervous system
cancer mortality
National Institute for
Occupational Safety and
Health (NIOSH) Cohort.
34494 workers at NY
microelectronics and business
machine facility. 2009. 52-
65yrs
Cumulative methylene
chloride exposure score
based on department-
exposure matrix
Methylene chloride was
not significantly associated
with mortality from brain
or other nervous system
cancers.
Medium
11
-------
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Cancer
Acute myeloid lymphoma
Cases of acute myeloid
leukemia (n= 14.337)
diagnosed between 1961 and
2005. and controls
(11=71.027) matched bv age.
sex. and country identified
from the Nordic Occupational
Cancer Study cohort
Cumulative methylene
chloride exposure estimated
using job exposure matrix.
Median (ppin-yr) 9.9
No significant increase in
acute myeloid leukemia
risk was observed with
low. moderate, or high
exposure to methylene
chloride, compared to
referent group, when
hazard ratios were
calculated using a 10-year
lag (p-valuc = 0.43).
Findings remained
statistically nonsignificant
when analysis was
stratified by sex or age
High
Methylene chloride
exposure was not
significantly associated
with mortalilv from:
Cancer
All malignant neoplasms
mortality
Male employees from
Brantham photographic film
base. United Kingdom.
n=1346 men (1034 exposed.
312 unexposed) exposed from
1960 - 1988
.Methylene chloride,
cumulative exposure,
median (1000 ppm-ycars)
36.0
all malignant neoplasms
(p-valuc = 0.60): brain
cancer (p-valuc=0.9):
respiratory cancer (p-
valuc=0.90): all cancers,
excluding respiratory
cancers (p-valuc=0.62): No
Cox regression coefficients
estimating relative risk
were statistically evaluated
Medium
Cancer
Lung cancer
Lung cancer cases and
randomly selected
popu la I ion-ba scd cont ro 1 s
frequency matched by sex
and age in Montreal Canada
Methylene chloride exposure
(any or substantial) was
assessed by a team of
industrial chemists and
hygicnisls based on self-
reported job histories.
No significant association
observed between any or
substantial exposure to
Methylene chloride and
lung cancer in the pooled
analysis (or either study
individually)
Medium
12
-------
T.iifyM Origin/
Sj Mom
Ouloomo/ l.ndpninl
Slmlj Population
l'l\|)OMIIV
Komi lis
Roforonoo
Diilii Qu;ili(\
l-'.\ iiliiiilion
Cancer
Non-Hodgkin Lymphoma
601 cases, 717 controls (all
women) in Connecticut,
1996-2000,21-84 years
Never, low, or medium-high
probability of exposure to
methylene chloride
Non-Hodgkin lymphoma
was associated with low
probability of exposure to
methylene chloride, but not
with medium-high
probability of exposure to
methylene chloride
Wang et al,
(2009)
Medium
Cardiovascular
Birth defects
Offspring of 60.613 case-
mothers and 244.927 control-
mothers in United States
(Texas)
Exposed or non-exposed:
exposure risk estimates
based on proximity of
maternal residence to
methylene chloride
emissions
A weak negative
association was observed
between exposure to
methylene chloride and
septal heart defects
Medium
Cardiovascular
Cause-specific mortality
1271 textile workers, Rock
Hill, South Carolina, 1954-
1986
Methylene chloride, 8-hour
TWA (ppm) 1700
Significant excess
mortality for accidents and
cancer of the biliary
passages & liver; all other
SMRs non-significant
Lanes et al,
CI 990")
Medium
Cardiovascular
Mortality associated with
cerebrovascular disease,
ischemic heart disease
Cellulose fiber production
workers (n=1271, Rock Hill,
South Carolina)
Methylene chloride in 1977
median of 140, 280, and 475
ppm in three main areas
Methylene chloride was
not significantly associated
with cardiovascular-related
mortality.
Lanes et al,
CI 993)
Medium
Cardiovascular
Chest discomfort with exercise
Adult employees of a
triacetate fibers plant
(n=150), 1984-1986, Rock
Hill, SC, and matched non-
exposed controls (n=260)
Methylene chloride, mean
475 ppm (8-hour time
weighted average), for
longer than 10 years
Occupational exposure to
methylene chloride for
more than 10 years did not
result in significant
differences in self-reported
cardiovascular symptoms
when comparing exposed
to unexposed workers
5ocienfl993)
Medium
13
-------
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Cardiovascular
Ischemic heart disease
mo rla lily
Male employees from
Branlham photographic film
base. United Kingdom.
n=1346 men (1034 exposed.
312 unexposed) exposed from
I960 - 1988
Methylene chloride,
cumulative exposure,
median (1000 ppm-ycars)
36.0
Methy lene chloride
exposure was not
significantly associated
with ischemic heart disease
mo rla lily (p-value=0.24);
No Cox regression
coefficients estimating
relative risk were
statistically evaluated
Medium
Growth (early life)
and Development
Low birthweight
91,302 live births from 1976
to 1987 in Monroe County,
New York among residents
living near the Eastman
Kodak Company
Kodak Air Management
Program (KAMP) air
dispersion modeling system:
high (50 ug/m), moderate
(25 ug/m), low (10 ug/m),
and none
A significant association
between exposure to
methylene chloride at all
three levels and low
birthweight was not
observed
Bell et al.
(1991)
High
Growth (early life)
and Development
Birth defects
Offspring of 60.613 casc-
molhcrs and 244.927 control -
mothers in United Stales
(Texas)
Exposed or non-exposed:
exposure risk estimates
based on proximity of
maternal residence to
methylene chloride
emissions
No significant association
was observed between
exposure to methylene
chloride and oral clefts
Medium
Growth (early life)
and Development
Spontaneous abortion
44 female pharmaceutical
factory workers in Finland
who had spontaneous
abortions while employed
(cases), 130 female
pharmaceutical factory
workers in Finland who had
normal births while employed
(controls)
Methylene chloride exposure
based on a questionnaire sent
to factory physicians or their
nurses
A positive, borderline non-
significant association was
observed between
occupational exposure to
methylene chloride and
spontaneous abortion
Taskinen et al,
CI 986)
Medium
14
-------
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Hematological and
Immune
Primary Sjogren sy ndrome
Cases (n= 175) from three
University Hospitals and
matched controls (n=350)
(2010-2013)
Occupational methylene
chloride exposure based on
sclf-rcportcd occupational
histories, expert judgement
of industrial hygicnists and
occupational practitioners, as
well as the French JEM
(used more for the
chlorinated solvents)
Significant increase in risk
for Sjogren' syndrome with
occupat iona 1 mclhv lene
chloride exposure: OR was
increased with high final
cumulative exposure, but
was not significant.
Medium
Hematological and
Immune
Total bilirubin, red cell count,
hemoglobin, hematocrit, mean
corpuscular volume, mean
corpuscular hemoglobin, mean
corpuscular hemoglobin
concentration,
carboxyhemoglobin, aspartate
aminotransferase, alanine
aminotransferase, lactate
dehydrogenase, alkaline
phosphatase, and
albumin.
266 exposed and 251
unexposed employees at two
fiber production plants in
North Carolina and Virginia
8 hour time-weighted
average dichloromethane
concentrations: unexposed,
60 and 140 ppm, 280 ppm,
and 475 ppm
There was a statistical
increase in aspartate
aminotransferase with
intensity of methylene
chloride exposure among
white women in the
exposed group, but not
among the white men, or
nonwhites of either sex.
Ott et al. (1983)
Medium
Hematological and
Immune
Hematocrit
Adult employees of a
triacetate fibers plant
(n=150), 1984-1986, Rock
Hill, SC, and matched non-
exposed controls (n=260)
Methylene chloride, mean
475 ppm (8-hour time
weighted average), for
longer than 10 years
Occupational exposure to
methylene chloride for
more than 10 years did not
result in a significant
difference in hematocrit
when comparing exposed
to unexposed workers
Socien (1993),
Medium
Hepatic
Scrum gamma glutamyl
transferase (GGT). scrum total
bilirubin, scrum aspartate
amino-transferase (AST),
scrum alanine aminotransferase
(ALT)
854 workers in a plastic
polymer facility in Indiana.
USA. i985
Methylene chloride: non-
exposed group (> 1.0 ppm).
low-exposed group (3.3
ppm). mcd-cxposcd group
(10.9 ppm). high-exposed
group (49.0 ppm)
Scrum gamma glutamyl
transferase (GGT). scrum
total bilirubin, scrum
aspartate amino-transferase
(AST), scrum alanine
aminotransferase (ALT)
Medium
15
-------
T.iifyM Origin/
Sj Mom
Ouloomo/ l.ndpninl
Slmlj Population
l'l\|)OMIIV
Komi lis
Roforonoo
Diilii Qu;ili(.\
l-'.\ iiliiiilion
Hepatic
Total bilirabin, red cell count,
hemoglobin, hematocrit, mean
corpuscular volume, mean
corpuscular hemoglobin, mean
corpuscular hemoglobin
concentration,
carboxyhemoglobin, aspartate
aminotransferase, alanine
aminotransferase, lactate
dehydrogenase, alkaline
phosphatase, and
albumin.
266 exposed and 251
unexposed employees at two
fiber production plants in
North Carolina and Virginia
8 hour time-weighted
average dichloromethane
concentrations: unexposed,
60 and 140 ppm, 280 ppm,
and 475 ppm
A consistent positively
significant association
between total bilirubin and
methylene chloride
exposure
was found in white men
and women, in non-white
women, but not in non-
white men.
Ott et al. (1983)
Medium
Hepatic
Mortality from cirrhosis and
other chronic liver disease
National Institute for
Occupational Safetv and
Health (NIOSH) Cohort.
34494 workers at NY
microelectronics and business
machine facility. 2009. 52-
65yrs
Cumulative methylene
chloride exposure score
based on department-
exposure matrix
Methylene chloride
exposure was not
significantly associated
with mortality from
diseases of the liver
Medium
Hepatic
Total bilirubin
Adult employees of a
triacetate fibers plant
(n=150), 1984-1986, Rock
Hill, SC, and matched non-
exposed controls (n=260)
Methylene chloride, mean
475 ppm (8-hour time
weighted average), for
longer than 10 years
Occupational exposure to
methylene chloride for
more than 10 years did not
result in significant
differences in markers of
hepatic injury when
comparing exposed to
unexposed workers
Soden(1993)
Medium
Mortality
Cause-specific, non-cancer
mortality
1271 textile workers, Rock
Hill, South Carolina, 1954-
1986
Methylene chloride, 8-hour
TWA (ppm) 1700
Significant excess
mortality for accidents
Lanes et al,
(1990)
Medium
16
-------
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Neurological/
Behavior
Birth defects
Offspring of 60.613 case-
mothers and 244.927 control-
mothers in United States
(Texas)
Exposed or non-exposed:
exposure risk estimates
based on proximity of
maternal residence to
methylene chloride
emissions
No significant association
was observed between
exposure to methylene
chloride and neural tube
defects
Medium
Neurological/
Behavior
Dizziness/vertigo
854 workers in a plastic
polymer facility in Indiana.
USA. i985
Methylene chloride: non-
exposed group (> 1.0 ppm).
low-exposed group (3.3
ppm). mcd-cxposcd group
(10.9 ppm). high-exposed
group (49.0 ppm).
There was significant trend
for increased
dizziness/vertigo in the
methylene chloride
exposed groups.
Medium
Neurological/
Behavior
Autism spectrum disorders
3.137 children in North
Carolina (1.931 total. 201
cases) and West Virginia
(1.246 total. 173 cases).
2000-2004. 8 years old
1996 modeled methylene
chloride in ambient air.
geometric mean
concentration: 539.8 (NC)
and 202..3 (WV) ng/mA3
A positive, non-significant
association between
ambient methylene
chloride (80th vs. 20th
percentile) and autism
spectrum disorder
High
Neurological/
Behavior
Grip strength, motor speed,
reaction time, visual memory,
verbal memory, attention,
spatial ability
25 retired mechanics (mean
age 67.5 yrs) who had
worked between 1970 and
1984 for a single, unspecified
airline; location not clearly
specified but appears to be
California
Mean time-weighted
averages of methylene
chloride (in air) ranged from
82 to 236 ppm
No statistically significant
differences in composite
scores between the
exposed and unexposed
groups
Lash et al,
(1991)
Medium
17
-------
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Neurological/
Behavior
Autism Spectrum Disorder
Nurses' Health Study II
children (US: 325
cases/22101 controls).
Methylene chloride air
concentrations at mother's
location at birth: Mean: 0.4
ug/m3
Methylene chloride
exposure was not
significantly associated
with Autism Spectrum
Disorder. Although it was
close to significant (p=0.05
forQl compared to Q5.
there was no trend over
quintilcs (p for trend
=0.08). When separated bv
sex. there was a significant
increase when comparing
Q5 to Q1 (p=0.03) in boys,
but not girls.
High
Neurological/
Behavior
Diseases of the nervous system
mortality
National Institute for
Occupational Safety and
Health (NIOSH) Cohort.
34494 workers at NY
microelectronics and business
machine facility. 2009. 52-
65yrs
Cumulative methylene
chloride exposure score
based on department-
exposure matrix
Methylene chloride
exposure was not
significantly associated
with mortality from
diseases of the nervous
system.
(Silver etal..
2014)
Medium
Neurological/
Behavior
Recurring severe headaches
Adult employees of a
triacetate fibers plant
(n=150), 1984-1986, Rock
Hill, SC, and matched non-
exposed controls (n=260)
Methylene chloride, mean
475 ppm (8-hour time
weighted average), for
longer than 10 years
Occupational exposure to
methylene chloride for
more than 10 years did not
result in significant
differences in self-reported
neurological symptoms
when comparing exposed
to unexposed workers
5ocien(1993)
Medium
18
-------
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Neurological/
Behavior
Autism spectrum disorder
diagnosis with Social
Communication Questionnaire
score of 15+
217 cases. 224 interview
controls. 4856 birth
certificate controls, children
born from 2005-2009 in 6
counties of Pennsylvania
Methylene chloride exposure
(239-273 ng/m3) during
gestation estimated with
National Air Toxics
Assessment 2005 model
from addresses at birth
Methylene chloride
positively associated with
Autism Spectrum Disorder
diagnosis relative to birth
certificate controls,
significant for fourth
quartilc compared to first
quartile of exposure for
singleton births, non-
significant for all births
combined.
Medium
Neurological/
Behavior
Autism diagnosis
Children (n=641 cases) born
to mothers living within 5 km
of air pollutant monitoring
stations in Los Angeles
County during pregnancy.
1995-2006. monitored until
age 6
Maternal ambient Methylene
chloride exposure during
entire pregnancy
A positive, non-significant
association was observed
between autistic disorder
by age 6 years and
maternal ambient
methylene chloride
exposure
High
Neurological/
Behavior
Autism Spectrum Disorder
Children born 1994 followed
for 9 years. 284 cases and 657
birth month- and sex-matched
control births from the San
Francisco area
1996 EPA estimated annual
average concentrations of
Methylene chloride on the
census tract level, mean
(SD) exposure for cases:
0.68 (0.48 ug/m3)
Positive association
observed for 3rd
(significant) and 4th (not
significant) quartilcs of
methylene chloride
exposure compared to
those exposed to the
median exposure level or
less.
Medium
Reproductive
Spontaneous abortion
Female pharmaceutical
factory workers in Finland.
44 cases, 130 controls, 1973-
1981
Methylene chloride exposure
based on a questionnaire sent
to factory physicians or their
nurses
Borderline significant
positive association
between occupational
methylene chloride
exposure and spontaneous
abortion
Taskinen et al.
Low
(1986)
19
-------
T.iifyM Origin/
Sj Mom
Ouloomo/ l.ndpninl
Slmlj Population
l'l\|)OMIIV
Komi lis
Roforonoo
Diilii Qu;ili(.\
l-'.\ iiliiiilion
Mortality
Accidents
1271 textile workers, Rock
Hill, South Carolina, 1954-
1986
Methylene chloride, 8-hour
TWA (ppm) 1700
Significant excess
mortality from accidents
Lanes et al,
(1990)
Medium
Respiratory
Mortality from nonmalignant
respiratory disease
Cellulose fiber production
workers (n=1271, Rock Hill,
South Carolina)
Methylene chloride in 1977
median of 140, 280, and 475
ppm in three main areas
SMR not elevated for non-
malignant respiratory
disease
Lanes et al,
(1993)
Medium
Respiratory
Mortality from bronchitis
Aircraft maintenance workers
(n = 14,457; 10,730 men and
3725 women) at Hill Air
Force Base (Utah, USA), for
at least one year from 1952-
1956, and followed up
through 2000
Occupational exposure to
methylene chloride (yes/no)
based on job-exposure
matrix; no quantitative
assessment available
Positive, statistically
significant, association
between mortality from
bronchitis in males and
occupational exposure to
methylene chloride
compared to no exposure
Radican et al,
(2008)
Medium
Respiratory
Mortality due to influenza and
pneumonia
Employees of a cellulose
acetate/triacetate fibers
plant (n=3211; 2187
men, 1024 women),
Cumberland, MD, 1970-
1989
Methylene chloride, area and
personal air samples taken at
a similar plant owned by the
same company
High occupational
exposure to methylene
chloride had a non-
significant positive
association with death
from influenza and
pneumonia men with
more than 20 years since
first exposure
Gibbs f 1992)
Medium
Respiratory
Mortality due to respiratory
illness
Male employees in
photographic film support
manufacturing (n=l,311),
Eastman Kodak Company,
Rochester, NY, 1946-1970
Methylene chloride, area and
personal air samples
Occupational exposure to
methylene chloride was
not significantly
associated with mortality
from respiratory diseases
Heame and
Pifer f 1999)
High
a Not identified in U.S. EPA (20.1.1): Identified through backwards searching from other sources or from TSCA submissions.
b Other mortality-related results are listed under the specific target organ or under cancer.
20
-------
2 Data Extraction Tables for Non-Cancer Endpoints From Animal Toxicity Studies
Noncancer endpoints/studies are divided into separate tables: (1) acute and short-term studies; (2) subchronic and chronic studies; and (3)
reproductive and developmental studies (and related effects from repeat-dose studies). They are divided by endpoint. Within each endpoint, data
from the inhalation exposure route is presented before the oral exposure route. Oral data are included because they are considered for the weight
of the scientific evidence.
The LOAELs and NOAELs are presented for each endpoint and study that measured that endpoint to compare across toxicity studies. For studies
cited in previous assessments, the NOAELs/LOAELs cited within that assessment are presented in the tables in this appendix. For newly-
obtained studies, EPA reports any NOAELs and LOAELs chosen by the study authors (if available); if EPA disagreed with the NOAEL/LOAEL,
a separate value is also presented below. The NOAELs/LOAELS are presented from lowest to highest for each endpoint and exposure route.
2.1 Acute and Short-term Animal Toxicity Studies a
T;ir;ii'( Or«i;in/
System
Suulj Tjpc
Speck's/
Sir;iin/Se\
(Nil in hoi'/
{•roup)
F.xpuslllV
Koulo
Doses/
( oiutm 1 ml inns
Dui'iilion
NOAI'.I./
1.OA F.I.
ivporiod l)\
Sliulj illllllOI'S
NOAFI./
1.OA F.I.
(inii/inJ or
mii/k*i-(l;i\)
FITccl
Rd'civnce
Diilii Qu;ili(>
F\ icin
Body Weight
Short-term
Rat M/F
(5/sex/group)
Oral
0, 100, 300, 600,
1200 mg/kg-
bw/day
7 days/week
for 14 days
Not Reported
LOAEL = 100
mg/kg-bw/day
i bodv weight
(M)
General
Electric
(1976b')
Medium
(2.0)
Gastrointestinal
Short-term
Rat Other
Both (5)
Oral
0, 100, 300, 600,
1200 mg/kg-
bw/dav
7 days/week
for 14 days
Not Reported
NOAEL = 300
mg/kg-bw/day
Blood/
congestion in
intestines and
stomach
(hemorrhage) of
dead animals
General
Electric
(1976b)
Medium
(2.0)
21
-------
Target Organ/
System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
NOAEL/
LOAEL
reported by
study authors
NOAEL/
LOAEL
(mg/m3 or
mg/kg-dav)
Effect
Reference
Data Quality
Evaluation
Hepatic
Acute/
Short-term
Rat.
Fischer 344
Inhalation,
vapor, whole
body
0, 1910,3910
ppm (1 day):
0. 1950.3870
ppm (10 day)
1 or 10 days:
6 hrs/day
Not Reported
LOAEL =
1950 ppm
(10 days)
1 day: no
effects
10 days: t#
eosinophils in
ccntrilobular
cells
Shell Oil
(1986)
High (1.5)
Hepatic
Acute/
Short-term
Mouse.
B6C3F1
Inhalation,
vapor, whole
body
0, 2010, 3710
ppm (1 day):
0, 1990, 3960
ppm (10 day)
1 or 10 days:
6 hrs/day
Not Reported
LOAEL =
1990 ppm
(10 days)
1 day: j liver wt
at 3710 ppm
10 days: t liver
wt at both
concentrations
Shell Oil
(1986)
High (1.5)
Immune
Acute/
Short-term
Mouse, CD-I
Inhalation
Acute:
0, 52, 95 ppm
Short-term:
0,51 ppm
Acute = 3 hrs
Short-term = 3
hrs/day for 5
days
Not Reported
NOAEL = 52
ppm
t mortality
(12.2%; p<
0.01) from S.
zooepidemicus;
i bacteriocidal
activity (by
12%; p< 0.001)
Aranyi et
al. (1986)
Medium (1.8)
Immune
Short-term
Rat, Sprague-
Dawley
Inhalation
0, 5187 ppm
6 hrs/day, 5
days/wk for 28
days
Not Reported
NOAEL = 5187
ppm
No change in
IgM response
after injection
with sheep red
blood cells
[J, spleen wts]
Warbrick
et al.
(2003)
High (1.3)
Neurological
Short-term
prc-lest
followed by
acute test
Rat. F344. M.
16 (pretest)
8/group (during
test)
Inhalation
Prc-lcsl: 2000
ppm
Test: 0. 2000
ppm
Prc-lcsl: 6
hrds/day: 3
days:
Test: 2.5-3.5
hrs
Not reported
LOAEL = 2000
ppm
Changes in
somatosensory
evoked
potentials
(cerebellum/
sensory cortex):
reduced EEG
power |acute|
Dow
(1988)
High (1.5)
22
-------
Target Organ/
System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
NOAEL/
LOAEL
reported by
study authors
NOAEL/
LOAEL
(mg/m3 or
mg/kg-day)
Effect
Reference
Data Quality
Evaluation
Neurological
Iclinical signs|
Acute/
Shorl-lcrm
Rat.
Fischer 344
Inhalation,
vapor, whole
body
0, 1910,3910
ppm (1 day):
0. 1950.3870
ppm (10 day)
1 or 10 days:
6 hrs/dav
Not Reported
Not Determined
10 days:
subdued:
reduced
response to
noise stimulus
Shell Oil
(1986)
High (1.5)
Neurological
Iclinical signs|
Acute/
Shorl-lcrm
Mouse.
B6C3F1
Inhalation,
vapor, whole
body
0, 2010,3710
ppm (1 day):
0, 1990, 3960
ppm (10 day)
1 or 10 days:
6 lvrs/day
Not Reported
Not Determined
10 days:
subdued at 1990
ppm during last
hr of
exposure/day:
Hyperactive
first 3 hrs at
3960 ppm and
then subdued
later during
exposure
Shell Oil
(1986)
High (1.5)
Neurological
Acute
Rat, F344, F
(n=8/group)
Oral, gavage
0, 101, 337, 1012
or 1889 mg/kg
Single dose
(evaluated 4
and 24 hours
after dosing)
NOAEL= 337
(F)
Functional
observational
battery (FOB)
neuro-muscular
and
sensorimotor
parameters
significantly
different from
controls
Moser et
al. (1995)
High (1.3)
Neurological
Short-term
Rat, F344, F
(n=8/group)
Oral, gavage
0, 34, 101, 337,
1012 or 1889
mg/kg-day
14 days
NOAEL= 101
(F)
Alterations in
FOB from day
4 (autonomic,
neuro-muscular,
sensorimotor,
excitability)
Moser et
al. (1995)
High (1.3)
23
-------
Target Organ/
System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Coneentrations
Duration
NOAEL/
LOAEL
reported by
study authors
NOAEL/
LOAEL
(mg/m3 or
mg/kg-dav)
Effect
Reference
Data Quality
Evaluation
Neurological
Shorl-lcrm
Ral Other Both
(5)
Oral
0, 100, 300, 600,
1200 mg/kg-
bw/day
7 days/ week
for 14 days
Not Reported
NOAEL = 100
mg/kg-bw/day
Decreased
general activity
General
Electric
(1976b)
Medium (2.0)
Respiratory
Shorl-lcrm
Ral Other Both
(5)
Oral
0, 100, 300, 600,
1200
mg/kg-bw/day
7 days/ week
for 14 days
Not Reported
NOAEL = 300
mg/kg-bw/day
Gross
abnormalities in
the lungs
(pulmonary
congestion) of
animals thai
died during the
study.
General
Electric
(1976b)
Medium (2.0)
Respiratory
Acute/
Shorl-lcrm
Rat.
Fischer 344
Inhalation,
vapor, whole
body
0, 1910,3910
ppm (1 day):
0. 1950.3870
ppm (10 day)
1 or 10 days:
6 hrs/day
Not Reported
NOAEL=
3870 ppm
(10 days)
No effects on
lung
Shell Oil
(1986)
High (1.5)
Respiratory
Acute/
Shorl-lcrm
Mouse.
B6C3F1
Inhalation,
vapor, whole
body
0, 2010,3710
ppm (1 dav):
0, 1990, 3960
ppm (10 day)
1 or 10 days:
6 hrs/dav
Not Reported
Not Determined
1 day: Selective
vacuolation and
pyknosis of
Clara cells in
bronchiolar
epithelium
10 days: No
effects
Shell Oil
(1986)
High (1.5)
Multiple organs
Shorl-lcrm
Dog M/F
(1/scx/dosc)
Oral (gavagc)
0, 25, 75, 150,
300 mg/kg-
bw/day
7 days/week
for 14 days
Not reported
Not Determined
Congestion - no
clear dose-
response: Cyst
in brain (at
lowest dose)
General
Electric
(1976a)
Low
(downgraded)
aAcute = < 1 day; Short-term = > 1 day - ^30 days
24
-------
2.2 Subchronic and Chronic Animal Toxicity Studies a
TsirfyM
Origin/
S\s(em
Sliulj Tjpe
Spocios/
S(r;iin/Se\
(Nil in hoi'/
group)
l-lxposure Roule
Doses/
(onecnlnilions
Dui'iilioii
NOAM./
1.OA l-'.l.
reported In
Sliulj illllllOI'S
NOAII./
1.OA l-'.l.
(inii/niJ or
in»/k»-(l;i>)
(Sex)
HITecl
Reference
Diilii Qu;ili(\
l-'.\iiliiiilion
Mortality
Chronic
Rat, Sprague
Dawley, M/F
(n~190/dose)
Inhalation, vapor,
whole body
0, 1755, 5264 or
12,283 mg/m3
(0, 500, 1500 or
3500 ppm)
6 hours/day,
5 days/week for
2 years
NA
NOAEL = 5264
mg/m3
(F)
t mortality
Burek et
al. (1984)
High (1.5)
Mortality
Subchronic
Rat, F344, M/F
(n=20/group)
Inhalation, vapor,
whole body
0, 1843, 3685,
7371, 14,742 or
29,483 mg/m3 (0,
525, 1050, 2100,
4200 or 8400
ppm)
6 hours/day,
5 days/week for
13 weeks
NA
NOAEL=
14,742 mg/m3
1/10 (M) and
1/10 (F) died
NTP
(1986)
High (1.3)
Mortality
Subchronic
Mouse,
B6C3F1, M/F
(n=20/group)
Inhalation, vapor,
whole body
0, 1843, 3685,
7371, 14,742 or
29,483
mg/m3
(0, 525, 1050,
2100, 4200 or
8400 ppm)
6 hours/day,
5 days/week for
13 weeks
NA
NOAEL=
14,742 mg/m3
4/10 (M) and
2/10 (F) died
NTP
(1986)
High (1.3)
Mortality
Chronic
Rat, Sprague
Dawley, M/F
(n=100/dose)
Oral, gavage
0, 100 or 500
mg/kg-day
4-5 days/week,
up to 64 weeks
NA
NOAEL = 100
mg/kg-bw/day
(M)
t mortality
(M/F) (M: stat.
signif.) led to
study
termination at
64 weeks
Maltoni et
al. (1988)
Medium
(1.9)
25
-------
TsirfyM
Origin/
S\s(em
Stiulj Tjpe
Spocios/
S(r;iin/Se\
(Nil in hoi'/
group)
l-lxposure Roule
Doses/
(onecnlnilions
Dui'iilioii
NOAII./
1.OA l-'.l.
reported In
Slliclj illllllOI'S
NOAII./
I.OAI'.I.
(mg/ui3 or
m»/k»-(l;i\)
(Sex)
r.lTecl
Reference
Diilii Qu;ili(\
l-'.\iiliiiilion
Mortality
Chronic
Mouse, Swiss,
M/F
(n=100/treated
group; 120/
control group)
Oral, gavage
0, 100 or 500
mg/kg-bw/day
4-5 days/ week,
up to 64 weeks
NA
NOAEL = 100
(M/F)
t Mortality
(M/F: stat.
signif.) led to
study
termination at
64 weeks
Maltoni et
al. (1988)
Medium (1.9)
Body weight
Subchronic
Rat, F344, M/F
(n=20/group)
Inhalation, vapor,
whole body
0, 1843, 3685,
7371, 14,742 or
29,483 mg/m3 (0,
525, 1050, 2100,
4200 or 8400
ppm)
6 hours/day,
5 days/week for
13 weeks
NA
NOAEL=
14,742
| Body weight
(M: 23%)
(F: 11%)
NTP
(1986)
High
(1.3)
Body Weight
Subchronic
Dog/Beagle
(M/F)
(4/sc.\/group)
Oral
0. 12.5. 50. 200
mg/kg-bw/day
90 days
Not Reported
NOAEL = 200
mg/kg-bw/day
No changes in
body weight
General
Electric
(1976)
High
(1.5)
Body weight
Develop-
mental
Rat, F344, F
(n=17-
21/group)
Oral, gavage
0,337.5 or 450
mg/kg-bw/day
Gestation days 6-
19
NA
NOAEL= 337.5
(F)
^Maternal
weight gain
Narotsky
and
Kavlock
(1995)
High
(1.4)
Gastro-
intestinal
Chronic
Mouse,
B6C3F1, M/F
(n=100/group)
Inhalation, vapor,
whole body
0, 7019 or
14,038 mg/m3 (0,
2000 or 4000
ppm)
6 hours/day,
5 days/week for
2 years
NA
NOAEL=7019
(M/F)
Stomach
dilation (M/F)
NTP
(1986)
High
(1.3)
Gaslroinlcsti
nal
Subchronic
Dog/Beagle
(M/F)
(4/sc.\/group)
Oral
0. 12.5. 50. 200
mg/kg-bw/day
90 days
Not Reported
NOAEL = 200
mg/kg-bw/day
No effects
General
Electric
(1976)
High
(1.5)
Immune
Chronic
Rat, F344, M/F
(n=100/group)
Inhalation, vapor,
whole body
0,3510, 7019 or
14,038 mg/m3
(0, 1000, 2000 or
4000 ppm)
6 hours/day,
5 days/week for
2 years
NA
NOAEL= 3510
(M)
Splenic fibrosis
NTP
(1986)
High (1.3)
26
-------
TsirfyM
Origin/
S\s(em
Stiulj Tjpe
Spocios/
S(r;iin/Se\
(Nil in hoi'/
group)
l'A|)OMIIV Roille
Doses/
(onecnlnilions
Dui'iilioii
NOAII./
1.OA l-'.l.
reported In
Slliclj illllllOI'S
NOAII./
I.OAI.I.
(mg/ui3 or
m»/k»-(l;i\)
(Sex)
I'.ITeel
Reference
Diilii Qu;ili(\
l-'.\iiliiiilion
Immune
Chronic
Mouse,
B6C3F1, MZF
(n=100/group)
Inhalation, vapor,
whole body
0, 7019 or
14,038 mg/m3
(0, 2000 or 4000
ppm)
6 hours/day,
5 days/week for
2 years
NA
NOAEL= 7019
(M)
Splenic
follicular
atrophy
NTP
(1986)
High (1.3)
Hepatic
Chronic
Rat, F344, M/F
(n=100/group)
Inhalation, vapor,
whole body
0,3510, 7019 or
14,038 mg/m3 (0,
1000, 2000 or
4000 ppm)
6 hours/day,
5 days/week for
2 years
NA
LOAF,L= 3510
(M/F)
Hepatocyte
vacuolation and
necrosis,
hemosiderosis
in liver (M/F);
hepatocyte-
megaly (F)
NTP
(1986)
High (1.3)
Hepatic
Chronic
Rat, Sprague-
Dawley, M/F
(n~190/group)
Inhalation, vapor,
whole body
0, 1755, 5264 or
12,283 mg/m3 (0,
500, 1500 or
3500 ppm)
6 hours/day,
5 days/week for
2 years
NA
LOAEL= 1755
(M/F)
Hepatocyte
vacuolation
(M/F);
multinucleated
hepatocytes (F)
Burek
(1984)
High (1.5)
Hepatic
Chronic
Rat, Sprague
Dawley, M/F
(n=180/group)
Inhalation, vapor,
whole body
0, 176, 702 or
1755 mg/m3 (0,
50, 200 or 500
ppm)
6 hours/day,
5 days/week for
2 years
NA
NOAEL= 702
(F)
Hepatic lipid
vacuolation and
multinucleated
hepatocytes
Nitschke
(1988)
High (1.3)
Hepatic
Chronic
Rat.
F344/DuCrj
Inhalation, vapor,
whole body
0. 3510. 7019 or
14.038 mg/m3 (0.
1000, 2000 or
4000 ppm)
6 hours/day.
5 days/week for
2 years
NA
LOAEL = 3510
mg/m.3 (F)
Increased
basophilic foci
and increased
abs/rcl liver wl
(p<0.01)
Aiso el al.
(2014)
High (1.1)
27
-------
TsirfyM
Origin/
S\s(em
Sliulj Tjpe
Spocios/
S(r;iin/Se\
(Nil in hoi'/
group)
r.\|)(isuiT Kouio
Doses/
(onecnlnilions
Dui'iilioii
NOAII./
1.OA l-'.l.
reported In
Sliulj illllllOI'S
NOAII./
I.OAI.I.
(in^/in3 or
)
(Sex)
IITecl
Reference
Diilii Qu;ili(\
l-'.\iiliiiilion
Hepatic
Chronic
Mouse,
B6C3F1, M/F
(n=100/group)
Inhalation, vapor,
whole body
0, 7019 or
14,038 mg/m3
(0, 2000 or 4000
ppm)
6 hours/day,
5 days/week for
2 years
NA
LOAEL = 7019
(F)
Hepatocyte
degeneration;
(t
hepatocellular
adenoma or
carcinoma)
NTP
(1986)
High (1.3)
Hepatic
Chronic
Mouse. Crj:
BDFi
Inhalation, vapor,
whole body
0.3510. 7019 or
14.038 mg/m' (0.
1000, 2000 or
4000 ppm)
6 hours/day.
5 days/week for
2 years
NA
NOAEL = 7019
mg/m.3 (F)
Increased
abs/rcl liver wl
(p < 0.01, <
0.05): non-ss
increase in
basophilic foci
(incidences of
1,1,3,5)
Aiso el al.
(201.4)
High (1.1)
Hepatic
Subchronic
Mouse,
B6C3F1, M/F
(n=20/group)
Inhalation, vapor,
whole body
0, 1843, 3685,
7371, 14,742 or
29,483
mg/m3
(0, 525, 1050,
2100, 4200 or
8400 ppm)
6 hours/day,
5 days/week for
13 weeks
NA
NOAEL= 7371
(F); NOAEL =
14,742 (M)
Hepatocyte
centrilobular
degeneration
NTP
(1986)
High (1.3)
28
-------
TsirfyM
Origin/
S\s(em
Sliulj Tjpe
Spocios/
S(r;iin/Se\
(Nil in hoi'/
group)
l'A|)OMIIV Roille
Doses/
(onecnlnilions
Dui'iilioii
NOAII./
1.OA l-'.l.
reported In
Sliulj illllllOI'S
NOAII./
I.OAI.I.
(mg/ui3 or
m»/k»-(l;i\)
(Sex)
I'.ITeel
Reference
Diilii Qu;ili(\
l-'.\iiliiiilion
Hepatic
Chronic
Rat, F344, M/F
(n=170/group +
270 controls)
Oral, drinking
water
0, 6, 52, 125 or
235 mg/kg-day
(M);
0, 6,58, 136 or
263 mg/kg-day
(F)
104 weeks
NA
NOAEL=6
(M/F)
t Non-
neoplastic
Foci/areas of
alteration
(M/F); t
incidence of
neoplastic
nodules; fatty
liver changes
(incidence
N/A)
Serota et
al. (1986a)
High (1.3)
Hepatic
Subchronic
Rat, F344, M/F
(n=30/group)
Oral, drinking
water
0, 166, 420 or
1200 mg/kg-day
(M);
0, 209, 607 or
1469 mg/kg-day
(F)
90 days
NA
LOAEL= 166
(M); LOAEL =
209 (F)
Hepatic
vacuolation
(generalized,
centrilobular,
or periportal)
Kirschman
et al.
(1986)
Low (2.5)
Hepatic
Chronic
Mouse,
B6C3F1, M/F
(n=125, 200,
100, 100 and
125 [M];
n=100, 100, 50,
50 and 50 [F])
Oral, drinking
water
0, 61, 124, 177
or 234 mg/kg-
day (M);
0, 59, 118, 172
or 238 mg/kg-
day (F)
104 weeks
NA
NOAEL= 185
(M/F)
Some evidence
of fatty liver;
marginal
increase in the
Oil Red-O-
positive
material in the
liver
Hazleton
Labs
(1983)
Medium (1.7)
Hepatic
Subchronic
Mouse,
B6C3F1, M/F
(n=30/group)
Oral, drinking
water
0, 226, 587 or
1911 mg/kg-day
(M);
0, 231,586 or
2030 mg/kg-day
(F)
90 days
NA
NOAEL= 226
(M)
Hepatic
vacuolation
(increased
severity of
centrilobular
fatty change)
Kirschman
(1986)
Low (2.5)
29
-------
TsirfyM
Origin/
S\s(em
Hepatic
Stiulj Txpe
Subchronic
Spocios/
S(r;iin/Sex
(N u in her/
group)
Dog/Beagle
(M/F)
(4/se.\/ group)
r.\|)(isuiT Route
Oral
Doses/
(onccnlmlions
0. 12.5. 50. 200
mg/kg-bw/day
Dui'iilioii
90 days
NOAII./
1.OA l-'.l.
reported In
Slliclj illllllOI'S
Not Reported
NOAII./
I.OAI'.I.
(mg/ui3 til'
m»/k»-(l;n)
(Sex)
NOAEL = 200
mg/kg-bw/day
IITecl
No changes in
clinical
chemist ry.
gross
pathology.
organ weight.
or
histopathologic
al lesions
Reference
General
Electric
(1976)
Diilii Qu;ili(\
l-'.\iiliiiilion
High
(1.5)
Neurological
Subchronic
Dog/Beagle
(M/F)
(4/se.\/ group)
Oral
0. 12.5. 50. 200
mg/kg-bw/day
90 days
Not Reported
NOAEL = 200
mg/kg-bw/day
No changes in
clinical
chemistry.
gross
pathology.
organ weight.
or
histopathologic
al lesions
General
Electric
(1976)
High
(1.5)
Renal
Chronic
Rat, F344, M/F
(n=100/group)
Inhalation, vapor,
whole body
0,3510, 7019 or
14,038 mg/m3
(0, 1000, 2000 or
4000 ppm)
6 hours/day,
5 days/week for
2 years
NA
NOAEL= 3510
(M); NOAEL =
7019 (F)
Renal tubular
degeneration
NTP
(1986)
Mennear
(1988)
High (1.3)
Renal
Chronic
Mouse,
B6C3F1, M/F
(n=100/group)
Inhalation, vapor,
whole body
0, 7019 or
14,038 mg/m3
(0, 2000 or 4000
ppm)
6 hours/day,
5 days/week for
2 years
NA
LOAEL= 7019
(F); NOAEL =
7019(M)
Renal tubule
casts
NTP
(1986)
High (1.3)
Respiratory
Chronic
Rat, F344, M/F
(n=100/group)
Inhalation, vapor,
whole body
0,3510, 7019 or
14,038 mg/m3
(0, 1000, 2000 or
4000 ppm)
6 hours/day,
5 days/week for
2 years
NA
NOAEL= 7019
(F)
Nasal cavity
squamous
metaplasia
NTP
(1986)
High (1.3)
30
-------
TsirfyM
Origin/
S\s(em
Sliulj Tjpe
Spocios/
S(r;iin/Se\
(Nil in hoi'/
group)
r.\|)(isuiT Kouii-
Doses/
(onecnlnilions
Dui'iilioii
NOAII./
1.OA l-'.l.
reported In
Sliulj illllllOI'S
NOAII./
I.OAI.I.
(mg/ui3 or
)
(Sex)
IITecl
Reference
Diilii Qu;ili(\
l'.\iiliiiilion
Respiratory
Subchronic
Rat, F344, M/F
(n=20/group)
Inhalation, vapor,
whole body
0, 1843, 3685,
7371, 14,742 or
29,483 mg/m3
(0, 525, 1050,
2100, 4200 or
8400 ppm)
6 hours/day,
5 days/week for
13 weeks
NA
NOAEL=
14,742
(M/F)
Foreign body
pneumonia
(focal
accumulation
of mononuclear
and
multinucleated
inflammatory
cells)
NTP
(1986)
High (1.3)
Respiratory
Subchronic
Mouse,
B6C3F1, M/F
(n=20/group)
Inhalation, vapor,
whole body
0, 1843, 3685,
7371, 14,742 or
29,483 mg/m3
(0, 525, 1050,
2100, 4200 or
8400 ppm)
6 hours/day,
5 days/week for
13 weeks
NA
NOAEL=
29,483
(M/F)
No
nonneoplastic
pulmonary
lesions
NTP
(1986)
High (1.3)
a Subchronic: > 30 - < 90 days; Chronic = > 90 days
31
-------
2.3 Reproductive and Developmental Outcomes from Animal Toxicity Studies
Tsirgi'l
Origin/
S\s(cm
Siiulj Tjpe
Species/
Sirsiin/Sex
(Nil in hoi'/
group)
l-lxposurc
Uoule
Doses/
(oncciilnilions
Dui'iilion
NOAI'.I./
1.OA l-'.l.
(inii/inJ or
m»/k;i-(l;i\)
(Sex)
r.lTeel
Reference
Diilii Qu;ili(\
l-'.\iiliiiilion
Body
weight
Developmental
Rat, F344, F
(n=17-
21/group)
Oral,
gavage
0,337.5 or 450
mg/kg-bw/day
Gestation
days 6-19
NOAEL=
337.5
(F)
^Maternal
weight gain
Narotsky
and Kavlock
(1995)
High (1.4)
Develop-
mental
Reproductive
Rat, Charles
River, M/F
(n=20/group)
Oral,
gavage
0, 25,75 or 225
mg/kg-bw/day
90 days
before
mating (10
days
between last
exposure and
mating
period)
NOAEL=
225
No effects on
pup survival,
F1body
weight,
hematology,
or clinical
chemistry (up
to 90 days of
age), or
histology of
tissues from
F1 offspring
General
Electric
(1976)
High (1.5)
Develop-
mental
Developmental
Rat, F344, F
(n=17-
21/group)
Oral,
gavage
0,337.5 or 450
mg/kg-day
Gestation
days 6-19
NOAEL=
450
No effect on
pup survival,
resorptions or
pup weight
Narotsky
and Kavlock
(1995)
High (1.4)
Repro-
ductive
Reproductive
Rat, Charles
River, M/F
(n=20/group)
Oral,
gavage
0, 25,75 or 225
mg/kg
90 days
before
mating; F1
offspring
received
same
treatment as
parents for
90 days
NOAEL=
225
(M/F)
No effects on
fertility index
or number of
pups per litter
General
Electric
(1976)
High (1.5)
32
-------
T.irgi'l
Origin/
Sjsiom
Siuclj Tjpe
Species/
S(r;iin/Sc\
(Nil in hoi'/
Urnii p)
l'l\|)OMIIV
Koulo
Doses/
(oiiiTiili'iilions
Diii'iilion
NOAI'.I./
1.OA l-'.l.
(inii/niJ or
in$>/k$>-(l:i>)
(Sox)
r.nwi
UiTcmuv
Diilii Qu;ili(\
l-'.\iiliiiilion
Repro-
ductive
Developmental
Rat, F344, F
(n=17-
21/group)
Oral,
gavage
0,337.5 or 450
mg/kg-day
Gestation
days 6-19
NOAEL=
450
(M/F)
No effect on
resorption
rate, number
of live litters,
implants or
live pups
Narotsky
(1995)
High (1.4)
Repro-
ductive
Reproductive
Mouse, Swiss
Webster, M
Inhalation,
vapor,
whole body
0, 103, 144,212
ppm
2 hrs/day, 5
days/week
for 6 weeks;
males then
mated with
unexposed
females
NOAEL =
103 ppm
I fertility
(80% vs.
95%)
(stat. sig. by
one test but
not a second;
see U.S. EPA
(2011)
Raje et al.
(1988)
Medium (2.0)
Repro-
ductive
Chronic
Mouse,
B6C3F1, M/F
(n=100/group
)
Inhalation,
vapor,
whole body
0, 7019 or
14,038 mg/m3
(0, 2000 or 4000
ppm)
6 hours/day,
5 days/week
for 2 years
NOAEL=
7019
(M)
Testicular
atrophy
NTP (1986)
High (1.3)
Repro-
ductive
Chronic
Mouse,
B6C3F1, M/F
(n=100/group
)
Inhalation,
vapor,
whole body
0, 7019 or
14,038 mg/m3
(0, 2000 or 4000
ppm)
6 hours/day,
5 days/week
for 2 years
LOAEL=
7019
(F)
Ovarian
atrophy
NTP (1986)
High (1.3)
33
-------
3 Data Extraction Tables for Animal Cancer Bioassays
The following tables focus on liver, lung and mammary tumors and other statistically significantly increased tumor types observed in
animal cancer bioassays.
3.1 Liver Tumor Data from Cancer Bioassays
Reference
Simin iind
Species
I'ApuMirc
1(111 (c
Sc\
r.\|)(>surc lc\cls
Tumor ij pc
Si^iiiric;iul
(losc-ivliilcd
(icnd
Si^iiiriciiul
p:iii'\\ ise
com p;i rison
r.xposiirc lc\cl
willi si^iiiriciiul
inciviiso
I);il;i Qu;ili(\
l'.\idiiiilioii
NTP (1986)
B6C3F1
mouse
Inhalation
M
0, 2000, 4000
ppm
Hepatocellular adenoma
or carcinoma
/
4000 ppm
High (1.3)
F
Hepatocellular adenoma
or carcinoma
y
y
> 2000 ppm
Aiso cl ;il.
(2014)
BDF1
mouse
Inhalation
M
0, 1000, 2000,
4000 ppm
H cpalocc 11 u la r adc no ma
or carcinoma
y
> 2000 ppm
High (1.1)
Hepatic hemangioma
y
y
4000 ppm
Hepatic hemangioma or
hcmangiosarcoma
y
-
-
F
H cpalocc 11 u la r adc noma
or carcinoma
y
> 1000 ppm
Hepatic hemangioma
y
-
-
Hepatic hemangioma or
hcmangiosarcoma
-
-
NTP (1986)
F344 rat
Inhalation
M
0, 1000, 2000,
4000 ppm
Liver tumors
-
-
-
High (1.3)
F
Liver tumors
-
-
-
Aiso cl ;il.
(2014)
F344/DuCrj
Inhalation
M
0, 1000, 2000,
4000 ppm
H cpalocc 1 lu la r adc no ma
or carcinoma
s/
-
-
High (1.1)
34
-------
Reference
Siniin iiml
Species
I'1\|)omii'c
ion (e
Sc\
F
r.\|)osurc lc\cls
Tumor l\pc
Liver minors
Si^iiiric;iul
dosc-ivliilcd
(icnd
Siiiiiil'icniH
p:iii'\\ ise
comparison
I'lxposurc le\ el
wiili si^niriciinl
iiici-e;ise
l);il;i Qu;ili(\
i:\iiliiiilion
Burek et al.
(1984)
SD rat
Inhalation
M
0, 500, 1500,
3500 ppm
Liver tumors
-
-
-
High (1.5)
F
Liver tumors
-
-
-
Nitschke et
al. (1988)
SD rat
Inhalation
M
0, 50, 200, 500
ppm
Liver tumors
-
-
-
High (1.3)
F
Liver tumors
-
-
-
Maltoni et
al. (1988)
SD rat
Inhalation
F
0, 100 ppm
Liver tumors
-
-
-
Medium (2.0)
Burek et al.
(1984)
Syrian
golden
hamster
Inhalation
M
0, 500, 1500,
3500 ppm
Liver tumors
~
~
~
High (1.5)
Hazleton
Labs (1983)
Serota et al.
(1986b)
B6C3F1
mouse
Oral (DW)
M
0, 61, 124, 177,
234 mg/kg-day
Hepatocellular adenoma
or carcinoma
± (p=0.058)
>124 mg/kg-day
Medium (1.7)
F
0, 59, 118, 172,
238 mg/kg-day
Hepatocellular adenoma
or carcinoma
-
-
-
Serota et al.
(1986a)
F344 rat
Oral (DW)
M
0, 6, 52, 125, 235
mg/kg-day
Hepatic neoplastic
nodule or hepatocellular
carcinoma
~
~
-
High (1.3)
F
0, 6, 58, 136, 263
mg/kg-day
Hepatic neoplastic
nodule or hepatocellular
carcinoma
58 and 263
mg/kg-day
35
-------
3.2 Lung Tumor Data From Animal Cancer Bioassays
Reference
Simin iind
Speck's
I'AposlllV
mule
Sc\
l'l\posui'c lc\cls
Tumor ij pc
Si<£iiiric;inl
dosc-rchili'd
(mid
Si^iiiriciiul
p:iii'\\ isc
comparison
Mxposmv k'M'l
willi si^niriciinl
inciviisc
l);il;i Qu;ili(\
l'.\idiiiilion
NTP (1986)
B6C3F1
mouse
Inhalation
M
0, 2000, 4000
ppm
Bronchoalveolar
adenoma or carcinoma
/
/
> 2000 ppm
High (1.3)
F
Bronchoalveolar
adenoma or carcinoma
> 2000 ppm
Aiso cl ;il.
(2014)
BDF1
mouse
Inhalation
M
0, 1000, 2000,
4000 ppm
Bronchoalveolar
adenoma or carcinoma
~
~
> 1000 ppm
TBD (1.1)
F
Bronchoalveolar
adenoma or carcinoma
~
~
> 2000 ppm
MP ( )
F344 ral
Inhalation
M
0, 1000, 2000,
4000 ppm
Lung tumors
-
-
-
High (1.3)
F
Lung tumors
-
-
-
Aiso cl ;il.
(2014)
F344/DuCrj
Inhalation
M
0, 1000, 2000,
4000 ppm
Lung tumors
-
-
-
High (1.1)
F
Lung tumors
-
-
-
Burek et al.
(1984)
SD rat
Inhalation
M
0, 500, 1500,
3500 ppm
Lung tumors
-
-
-
High (1.5)
F
Lung tumors
-
-
-
Nitschke et
al. (1988)
SD rat
Inhalation
M
0, 50, 200, 500
ppm
Lung tumors
-
-
-
High (1.3)
F
Lung tumors
-
-
-
Maltoni et
al. (1988)
SD rat
Inhalation
F
0, 100 ppm
Lung tumors
-
-
-
Medium (2.0)
Burek et al.
(1984)
Syrian
golden
hamster
Inhalation
M
0, 500, 1500,
3500 ppm
Lung tumors
~
~
~
High (1.5)
36
-------
3.3 Mammary Gland Tumors from Animal Cancer Bioassays
Reference
Simin
iind
Species
l-lxposurc
mule
Sex
Doses 2000 ppm
Aiso cl ill.
(2014)
F344/Du
Crj
Inhalation
M
0, 1000, 2000, 4000
ppm
Mammary gland fibroadenoma
~
y
4000 ppm
High (1.1)
Mammary gland fibroadenoma or
adenoma
y
4000 ppm
Mammary gland fibroadenoma or
adenoma or adenocarcinoma
~
-
F
Mammary gland fibroadenoma
~
-
Mammary gland fibroadenoma or
adenoma
•/
-
Mammary gland fibroadenoma or
adenoma or adenocarcinoma
-
Burek et al.
(1984)
SD rat
Inhalation
M
0, 500, 1500, 3500
ppm
Mammary tumors
-
-
-
High (1.5)
F
Mammary tumors
- (dose-related t
no. tumors/
tumor-bearing
rat)
37
-------
Reference
Sii-iiin
and
Species
I'ApoMirc
ion (e
Sc\
Doses or
( onceiili'iilioiis
Tumor ij pe
Si^iiiriciiul
dose-related
(lend
Significant
paiiwise
com pari son
Dose or
coiicciili'iiliou
willi significant
increase
Data
Qnali(\
l-'.\ alnalion
\llsclll\C Cl
al. (1988)
SI) ral
Inhalation
\1
ii, 5", 2(1(1, 5(i(i ppni
Mammal's fibroma, fibrosarcoma, or
undifferentiated sarcoma
-
-
-
MigliO^
F
Benign mammary tumors
- (dose-related t
no. tumors/
tumor-bearing
rat)
Maltoni et al.
(1988)
SD rat
Inhalation
F
0, 100 ppm
Mammary tumors
-
-
-
Medium
(2.0)
Burek et al.
(1984)
Syrian
golden
hamster
Inhalation
M
0, 500, 1500, 3500
ppm
Mammary tumors
~
~
~
High (1.5)
38
-------
3.1 Other Tumor Data From Animal Cancer Bioassays
Reference
Sii-iiin
iind
Species
l'l\posui'c
ion (e
Sc\
Doses or
( onceiili'iilioiis
Tumor ij pe
Si^uiriciiiil
dosc-rchilcd
(lend
Siiiiiil'iciiiH
p:iii'\\ ise
comparison
Dose or
concenli'iilion
with si^niliciinl
increase
Diilii
Qn;ili(\
l-'.\ idiiiilion
NTP (1986)
B6C3F1
mouse
Inhalation
M
0, 2000, 4000 ppm
Hemangioma or hemangiosarcoma,
any site
-
y
4000 ppm
High (1.3)
F
Hemangioma or hemangiosarcoma,
any site
-
-
-
Aiso cl ;il.
(2014)
BDF1
mouse
Inhalation
M
0, 1000, 2000, 4000
ppm
Adrenal gland phcochromocvloma
~
-
-
High (1.1)
F
Adrenal gland phcochromocvloma
-
-
-
NTP (1986)
F344 rat
Inhalation
M
0, 1000, 2000, 4000
ppm
Subcutaneous fibroma or
fibrosarcoma
y
4000 ppm
High (1.3)
Mesothelioma (all sites)
y
2000 ppm
F
Subcutaneous fibroma or
fibrosarcoma
-
-
-
Aiso cl ;il.
(2014)
F344/
DuCrj
Inhalation
M
0, 1000, 2000, 4000
ppm
Subcutaneous fibroma
y
y
> 2000 ppm
High (1.1)
Subcutaneous fibroma or
fibrosarcoma
y
y
> 2000 ppm
Mesothelioma (peritoneal)
y
-
-
Mononuclear cell leukemia
-
-
-
F
Subcutaneous fibroma
-
-
-
Subcutaneous fibroma or
fibrosarcoma
-
-
-
Mcsothc 1 io ma (peri to nca 1)
-
-
-
Mononuclear cell leukemia
y
(only at 2000
ppm)
-
39
-------
Reference
Sii-iiin
iind
Speck's
l'l\pnsurc
ion (e
Sc\
Doses or
( onceiili'iilioiis
Tumor ij pe
Si^iiiriciiul
(lose-rehi led
(lend
Siiiiiil'ic;in(
p:iii'\\ ise
comparison
Dose or
conccnli'iilion
with si^niriciinl
increase
Diilii
Qn;di(\
l-'.\ iiliiiiiion
Endometrial stromal polyp
/
-
-
Endometrial stromal sarcoma or
leiomyosarcoma
/
-
-
Burek et al.
(1984)
SD rat
Inhalation
M
0, 500, 1500, 3500
ppm
Salivary gland sarcomas
NR
-
High (1.5)
F
Salivary gland sarcomas
-
-
-
Hazleton
Labs (1983)
Serota et al.
(1986b)
B6C3F1
mouse
Oral (DW)
M
0,61, 124, 177, 234
mg/kg-day
Mammary tumors
-
-
-
Medium
(1.7)
F
0,59, 118, 172, 238
mg/kg-day
Mammary tumors
-
-
-
Serota et al.
(1986a)
F344 rat
Oral (DW)
M
0, 6, 52, 125, or
235 mg/kg-day
Mammary tumors
-
-
-
High (1.3)
F
0, 6, 58, 136, or
263 mg/kg-day
Mammary tumors
-
-
-
40
-------
4 4 Data Extraction Tables for Genotoxicity Studies
4.1 Methylene Chloride Genotoxicity Studies not Cited in the 2011 IRIS Assessment
Species
Methylene Chloride Exposure
Outcome
Comments
Reference
Data Quality
Evaluation
Route
Dose/Duration
Humans:
workers in
pharmaceutical
industry
Inhalation/
dermal most
likely
8 hrs/day for > 8 months
of irregular PPE use
followed by 8 months of
strict PPE use (same 16
worker volunteers for
both phases)
Irregular PPE: Micronuclei,
nuclear buds and nucleoplasms
bridges were higher in blood
lymphocytes of workers exposed
to multiple chemicals than
controls. Tail length and percent
DNA in tail of comet assay did
not significantly differ from
controls in blood leukocytes.
Workers were exposed to other
possible carcinogens in
addition to methylene chloride:
phenylhydrazine, ethylene
oxide, 1,2-dichlorethane; Strict
PPE: some effects significantly
decreased compared with
irregular PPE after the strict
use of PPE was implemented
Zeliezic et al. f2016)
NE
Mice: B6C3F1
males
Inhalation
0,400, 800,1600 ppm; 6
hrs/day, 5 days/week for
6 weeks
Total red blood cells - no
increase in pig-A mutant
frequencies Reticulocytes or
normochromatic erythrocytes -
no increase in micronuclei
Authors note that the results are
indicative of lack of mutagenic
potential in hematopoietic stem
cells, and lack of
clastogenicity/ aneugenicity in
bone marrow of mice
Suzuki et al. (2014)
High
Mice: gpt Delta
C57BL/6J males
0, 800 ppm; 6 hrs/day, 5
days/week for 4 weeks
Liver - no increase in DNA
damage via comet assay or gpt
mutations
DNA damage and gpt
mutations were increased after
co-exposure of methylene
chloride and 1,2-
dichloropropane, suggesting
that the mutagenic potential of
1,2-dichloropropane may be
enhanced by methylene
chloride
41
-------
Species
Methylene Chloride Exposure
Outcome
Comments
Reference
Data Quality
Evaluation
Route
Dose/Duration
Rats: F344 gpt
delta
Gavage
0,250 or 500 mg/kg-bw
via gavage in corn oil
every day for 4 weeks
No increase in Gpt and Spi-
mutation frequencies; no
changes in gene or protein
expression of GST-T1 or
CYP2E1
The gpt delta rats carry
approximately 10 copies of the
transgene lambda EG10 per
haploid genome
Hirata et al. (2016)
High
Rats: Normal rat
kidney (NRK)
52E cell line
In vitro assay
50 to 5000 mg/L (comet
assay); 10 to -10,000
mg/L (cytotoxicity -
MTT - viability); 10 to
1000 mg/L (apoptosis
assay); 5000 mg/L (cell
cycle analysis)
DNA damage at 5 x 103mg/L (p
< 0.05) via comet (SCGE) assay;
no increased cytotoxicity
(MTT/cell viability or apoptotic
cells); no changes in cell cycle
None
Yang et al. (2014)
High
S. typhimurium
TA100
In vitro
reverse
mutation
assay
Up to 3500 ppm vapor
concentration
Increased revertants/plate and
increased mutation rate
No metabolic activation used;
method modified for evaluation
of volatile compounds
Mimaki et al. (2016)
High
S. typhimurium
TA98, TAIOO
In vitro
reverse
mutation
assay
Not reported
Increased revertants in the
presence of activation
Methods and procedures were
cited to other publications
Khudolev etal. (1987)
Medium
42
-------
4.2 Results from in vitro Genotoxicity Assays of Dichloromethane in Nonmammalian Systems
Kiulpoinl
Tesl System
Dosc/Conccnlnilion :tiul
Dm nil ion
Resi
—S9
ills"
+S1)
Com mollis
Reference
K\ iiliiiilion
Reverse
mutation
Salniont'lla
typhimurium TA98,
TA100
48-hr exposure to 0. 5.700.
11,400, 17,100, 22,800, and
57,000 ppm
+
(DR)
(DR)
Vapor phase exposure in enclosed 37°C
system. Toxic at highest dose only.
(1978)
I Iigli
Reverse
mutation
S. typhimurium
TA100
6-hr exposure to 0, 3,500,
7,000, and 14,000 ppm
+
(DR)
++d
(DR)
Vapor phase exposure in enclosed 37°C
system.
Joneen et al,
CI 982)
High
Reverse
mutation
S. typhimurium
TA100
3-day exposure, up to 84,000
ppm
+
+e
Vapor phase exposure in sealed jars.
Peak response at 12 h. Exogenous GST
or GSH had no effect.
Green (1983)
Medium
Reverse
mutation
S. typhimurium
TA100, TA98
24-hr exposure to 0, 0.01, 0.05,
0.1, 0.25, 0.5, and 1.0
mL/chamber
+
(DR)
++f
(DR)
Vapor phase exposure in sealed
desiccator jars required for positive
result. Toxicity at highest dose only.
Zeieer f 1990)
High
Reverse
mutation
S. typhimurium
TA100
S. typhimurium
TA100,NG54
E. coli WP2 uvrA
pKMlOl
2- and 6-hr exposures to 0,
2,500,5,000,7,500,10,000
ppm; 6- and 48-hr exposures up
to 50,000 ppm
6-hr exposure to 0, 2,500,
5,000,7,500,10,000,20,000,
40,000 ppm
6- and 48-hr exposures to
6,300,12,500, 25,000, and
50,000 ppm
+
(DR)
+
(DR)
+
(DR)
+g
(DR)
+
(DR)
+
(DR)
Vapor phase exposure in sealed jars.
NG54=TA100 with 4-fold lower GSH
levels. Exogenous GSH slightly
increased mutation frequency. Peak
response at 6 h.
Dillon et al, f 1992)
High
Reverse
mutation
S. typhimurium
TA1535 (+GST5-5)
TA1535
0-2.0 mM/plate
+
(DR)
ND
ND
5 min preincubation. Transfected with
rat GST5-5. Negative with exogenous
S-(l-acetoxymethyl)GSH or HCHO.
Parental strain negative with exogenous
GSH or GST.
Thieret al, (1993)
Medium
Reverse
mutation
S. typhimurium
TA100
NG-11
3-day exposure, up to 100,000
ppm
++
(DR)
+
(DR)
ND
ND
Vapor phase exposure in sealed jars.
NG-11=TA100 without GSH; adding
GSH increased mutagenicity of NG-11.
Toxic at highest dose.
Graves et al,
f1994a)
High
43
-------
Kndpoint
Test System
Dose/Concent ration and
Duration
Rest
-SO
¦ Its'
+S1)
Comments
Reference
Data Quality
K\ alualion
Reverse
mutation
S. ivpliimiiriiim
TA1535 (+GST5-5)
TA1535
0. 200. 400. 800. and 1600 ppm
(0,0.03, 0.06, 0.13, and 0.26
mM in medium)
+
(DR)
-(T)
Nl)
ND
Plate incorporation assay: 24 h
exposure in sealed Tedlar bags.
Transfected with rat GST5-5. Toxic at
highest dose.
(1997)
I Iigli
Forward
mutation
S. typhimurium
TA100, RSJ100
TA1535, TPT100
Up to 24,000 ppm
+
-(T)
ND
ND
Plate incorporation assay; 24 h
exposure in sealed Tedlar bags.
RSJ100=TA153 5+transfected rat
GSTT1-1; TPT100= nonfunctional
GSTT1-1 gene. Toxic at highest dose.
Demarini et al,
(1997)
High
Forward
mutation
S. typhimurium
BA13
0, 8, 20,40, and 85 |xmol/plate
+++
+c
Preincubation assay for L-arabinose
resistance (AraR test). Toxic >85 pmol.
Roldan-Ariona and
Puevo(1993)
High
Forward
mutation
E. coli K12 (wild
type)
E. coli UvrA
2-hr exposures to 0, 30, 60, and
130 mM/plate (aqueous
concentrations)
+h
Vapor phase exposure in sealed jars.
"+" with mouse liver S9 only, not rat.
No cell death in these strains and doses.
Graves et al,
(1994a)
High
Fungi and yeasts
Mitotic
segregation
Aspergillus nidulans
-diploid strain PI
0, 800, 2,000, 4,000, 6,000, and
8,000 ppm
+ (T)
ND
Positive only at 4,000 ppm.
Crebelli et al,
(1988)
High
Gene
conversion
Mitotic
recombination
Reverse
mutation
Saccharomyces
cerevisiae
-strain D7
0, 104, 157, and 209 mM
+ (T)
+ (T)
+ (T)
(DR)
ND
ND
ND
Total cell death at 209 mM. Positive at
157 mM only with 58% cell death.
Positive dose-response at 104 and 157
mM.
Callen et al, (1980)
High
H- = positive, - = negative, (T) = toxicity, ND = not determined, DR = dose-response observed.
b S9 liver fraction isolated from male Wistar rats induced with phenobarbital.
c S9 liver fraction isolated from rats induced with Aroclor 1254.
d S9 liver fraction isolated from male Wistar rats induced with Aroclor 1254 and phenobarbital and separated into microsomal and cytosolic fractions.
e S9 liver fraction isolated from male Sprague-Dawley rats induced with Aroclor 1254 and separated into microsomal and cytosolic fractions.
f S9 liver fraction isolated from male Sprague-Dawley rats induced with Aroclor 1254.
g S9 liver fraction isolated from male Fischer F344 rats induced with Aroclor and separated into microsomal and cytosolic fractions.
h S9 liver fractions isolated from male B6C3F1 mice or male Alpk:APfSD (AP) rats.
Source: U.S. EPA ( ), Table 4-20, pp. 104-106
44
-------
4.3 Results from in vitro Genotoxicity Assays of Dichloromethane with Mammalian Systems by
Test Type
Assay
Test System
C On coil I rn I i on s
Results
Reference
Data Quality
K\ aliialion
Human
Micronucleus test
Human AHH-1,
MCL-5, h2El cell
lines
Up to 10 mM
Positive in MCL-5, h2El cell lines, increasing with
increasing concentrations from 2 to 10 mM
Dohertv et al, ( 1996)
High
DNA damage by comet
assay
Primary human lung
epithelial cells
10,100,1,000 pM
Weak trend, independent of GST activity (GST
enzymatic activity not present in the cultured cells)
Landi et al, (2003)
Medium
DNA SSBs by alkaline
elution
Human hepatocytes
5-120 mM
Negative. Cytotoxicity >90 mM as measured by
Trypan blue exclusion assay.
Graves et al, (1995)
High
Sister chromatid
exchange
Primary human
peripheral blood
mononuclear cells
0,15,30, 60,125,
250, 500 ppm
Sister chromatid exchanges significantly increased at
exposures of 60 ppm and higher, most strongly in the
high GST-T1 activity group; Mitotic indices decreased
in a dose-dependent manner); changes in cell
proliferation kinetics
Olvera-Bello et al, (2010)
High
DNA-protein cross-links
Human hepatocytes
0.5-5 mM
Negative
Casanova et al, (1997)
High
Mouse
DNA breaks by alkaline
elution
Mouse hepatocytes
(B6C3F1)
0, 0.4,3.0, 5.5 mM
Positive with dose-response. No toxicity at these doses
as measured by trypan blue exclusion assay.
Graves et al, (1994b)
High
DNA SSBs by alkaline
elution
Mouse Clara cells
(B6C3F1)
0, 5, 10, 30, 60 mM
Positive with dose-response; DNA damage reduced by
addition of GSH depletor. No toxicity at these doses as
measured by trypan blue exclusion assay.
Graves et al, (1995)
High
DNA-protein cross-links
Mouse hepatocytes
(B6C3F1)
0.5-5 mM
Positive
Casanova et al, (1997)
High
Rat
DNA SSBs by alkaline
elution
Rat hepatocytes
(Alpk:APfSD [AP])
0, 30, 60, 90 mM
Positive with dose-response. Cytotoxicity at 90 mM as
measured by trypan blue exclusion assay.
Graves et al, (1994b)
High
DNA-protein cross-links
Rat hepatocytes
(Fischer-344)
0.5-5 mM
Negative
Casanova et al, (1997)
High
45
-------
Assay
Test System
Concent rations
Results
Re Terence
Data Quality
K\ aluation
Hamster with GST activity from mouse
hprt mutation analysis
CHO cells
3,000 and 5,000
ppm
Positive with mouse liver cytosol
Graves and Green f 1996)
High
hprt mutation analysis
CHO cells
2,500 ppma
Mutation spectrum supports role of glutathione
conjugate
Graves et al, (1996)
High
DNA SSBs and DNA-
protein cross-links
CHO cells
3,000 and 5,000
ppm
Positive at concentration of 0.5% (v/v) for SSBs in
presence of mouse liver cytosol, but increase in DNA-
protein cross-links marginal; formaldehyde (in absence
of mouse liver cytosol) was positive at 0.5 mM for
both DNA SSBs and DNA-protein cross-links; CHO
cell cultures were suspended
Graves and Green f 1996)
High
Comet assay
Chinese hamster V79
lung fibroblast cells
transfected with
mouse GST-T1
2.5, 5,10 mM
A significant, dose-dependent increase in DNA
damage resulting from DNA-protein cross-links in V79
cells transfected with mouse GST-T1 compared to
parental cells
Hu et al, (2006)
High
DNA-protein cross-links
CHO cells (Kl)
60 mM
Positive only with mouse liver S9 added; formaldehyde
positive at lower concentrations (0.5^1 mM)
Graves et al, (1994b)
High
Hamster without GST activity from mouse
Chromosomal
aberrations
CHO cells
2-15 (il/ml
Positive, independent of rat liver S9
Thilagar and Kumaroo (1983)
High
Forward mutation (hgprt
locus)
Chinese hamster
epithelial cells
10,000,20,000,
30,000, 40,000 ppm
Negative, without metabolic activation
(Experiment was not run with metabolic activation)
Joneenet al, (1981)
Medium
DNA SSBs by alkaline
elution
Syrian golden hamster
hepatocytes
0.4-90 mM
Negative. Cytotoxicity at 90 mM as measured by
Trypan blue exclusion assay.
Graves et al, (1995)
High
Sister chromatid
exchange
Chinese hamster V79
cells
10,000,20,000,
30,000, 40,000 ppm
Weak positive with or without rat-liver microsomal
system
Joneenet al, (1981)
High
Sister chromatid
exchange
CHO cells
2-15 (il/ml
Negative with or without rat liver S9
Thilagar and Kumaroo (1983)
High
DNA-protein cross-links
Syrian golden hamster
hepatocytes
0.5-5 mM
Negative
Casanova et al, (1997)
High
46
-------
Assay
Test System
Concent rations
Results
Role rcn cc
Data Quality
K\ aluation
Calf
DNA adducts
Calf thymus DNA
50 mM
Positive in the presence of bacterial GST DM11 and
dichloromethane dehalogenase; adducts primarily
formed with the guanine residues
Kavser and Vuilleumier (2001)
High
DNA adducts
Calf thymus DNA
Up to 60 mM
Positive in the presence of bacterial GST DM11, rat
GST5-5, and human GSTT11; adducts primarily
formed with the guanine residues
Marscfa et al, (2004)
High
CHO = Chinese hamster ovary; hprt = hypoxanthine-guanine phosphoribosyl transferase
^Methods section described concentration as 3,000 ppm (0.3%v/v) but Table I describes it as 2,500 ppm (0.25% v/v).
Source: U.S. EPA ( ), Table 4-21, pp. 108-110
47
-------
4.4 Results from in vivo Genotoxicity Assays of Dichloromethane in Insects
Assnv
Test System
Doses
Result
Reference
Diilii Quality
K\ iiliintion
Gene mutation (sex-linked
recessive lethal)
Drosophila
125, 620 mM
Positive (feeding exposure)
Gocke et al, (1981)
High
Gene mutation (sex-linked
recessive lethal, somatic
mutation and
recombination)
Drosophila
6hrs—1,850, 5,500 ppm
1 wk—2,360, 4,660 ppm
2 wks—1,370, 2,360 ppm (all
approximate)
Negative (inhalation exposure)
Kramers et al, f 1991)
High
Somatic w/w+ assay
Drosophila
50, 100,250, 500 mM
Positive (feeding exposure)
Rodrieuez-Amaiz f 1998)
Medium
Source: U.S. EPA ( ), Table 4-22, p. 114
48
-------
4.5 Results from in vivo Genotoxicity Assays of Dichloromethane in Mice
Asssiy
Test System
Route itiul Dose
Dm ml ion
Results
Reference
Diitii Quality
K\ iiliiiition
Kris and I Iras
oncogenes
Mouse liver and lung
tumors (B6C3F1)
0. 2.000 ppm
Up to 104 wks
No difference in mutation
profile between control and
dichloromethane-induced liver
tumors; number of spontaneous
lung tumors (n = 7) limits
comparison at this site
I Iigli
p53 tumor suppressor
gene
Mouse liver and lung
tumors (B6C3F1)
0, 2,000 ppm
Up to 104 wks
Loss of heterozygosity
infrequently seen in liver tumors
from exposed or controls;
number of spontaneous lung
tumors (n = 7) limits comparison
at this site
Hegi et al, ( 1993)
High
Micronucleus test
Mouse bone marrow
(C57BL/6J/Alpk)
Gavage, 1,250,2,500,
and 4,000 mg/kg
Single dose
Negative at all doses
Sheldon et al. (1987)
High
Micronucleus test
Mouse peripheral red
blood cells (B6C3F1)
Inhalation 6 hr/d, 5
d/wk, 0,4,000, 8,000
ppm
2 wk
Positive at 4,000 and 8,000 ppm
Allen et al, (1990)
High
Micronucleus test
Mouse peripheral red
blood cells (B6C3F1)
Inhalation, 6 hr/d, 5
d/wk, 0,2,000 ppm
12 wks
Positive at 2,000 ppm
Allen et al, (1990)
High
Chromosome
aberrations
Mouse bone marrow
(C57BL/6J)
Intraperitoneal, 100,
1,000,1,500,2,000
mg/kg
Single dose
Negative
Westbrook-Collins et al,
(1990)
High
Chromosome
aberrations
Mouse bone marrow
(B6C3F1)
Subcutaneous, 0, 2,500,
5,000 mg/kg
Single dose
Negative
Allen et al, (1990)
High
Chromosome
aberrations
Mouse lung and bone
marrow cells (B6C3F1)
Inhalation, 6 hr/d, 5
d/wk,
0, 4,000, 8,000 ppm
2 wks
Increase beginning at 4,000 ppm
in lung cells; increase only at
8,000 ppm in bone marrow cells
Allen et al, (1990)
High
DNA SSBs by
alkaline elution
Mouse hepatocytes
(B6C3F1)
Inhalation, 2,000 and
4,000 ppm
3 or 6 hrs
Positive at 4,000 ppm at 3 and 6
hrs
Graves et al, (1994b)
Medium
DNA SSBs by
alkaline elution
Mouse liver and lung
homogenate (B6C3F1)
Liver: inhalation, 2,000,
4,000, 6,000, 8,000 ppm
Lung: inhalation, 1,000,
2,000,4,000, 6,000 ppm
3 hrs
3 hrs
Liver: positive at 4,000-8,000
ppm
Lung: positive at 2,000^1,000
ppm
Graves et al, (1995)
High
49
-------
Asssiy
Test System
Route :iiul Dose
Dm ml ion
Results
Reference
D:it;i Qiiiility
K\ iiliiiition
DNA damage by
comet assay
Mouse stomach, urinary
bladder, kidney, brain,
bone marrow (CD-I)
Gavage, 1,720 mg/kg;
organs harvested at 0
(control), 3, and 24 hrs
Single dose
Negative 3 or 24 hr after dosing
Sasaki et al, ( 1998)
High
DNA damage by
comet assay
Mouse liver and lung cells
(CD-I)
Gavage, 1,720 mg/kg;
organs harvested at 0
(control), 3, and 24 hrs
Single dose
Positive only at 24 hrs after
dosing
Sasaki et al, ( 1998)
High
DNA adducts
Mouse liver and kidney
cells (B6C3F1)
Intraperitoneal, 5 mg/kg
Single dose
Negative
Watanabe et al. (2007)
Medium
DNA-protein cross-
links
Mouse liver and lung cells
(B6C3F1)
Inhalation, 6 hr/d, 3 d,
4,000 ppm
3 d
Positive in mouse liver cells at
4,000 ppm; negative in mouse
lung cells
Casanova et al, (1992)
High
DNA-protein cross-
links
Mouse liver and lung cells
(B6C3F1)
Inhalation, 6 hr/d, 150,
500,1,500,3,000,4,000
ppm
3 d
Positive in mouse liver cells at
500^1,000 ppm; negative in
mouse lung cells
Casanova et al, (1996)
High
Sister chromatid
exchange
Mouse bone marrow
(C57BL/6J)
Intraperitoneal, 100,
1,000,1,500,2,000
mg/kg
Single dose
Negative
Westbrook-Collins et al,
(1990)
High
Sister chromatid
exchange
Mouse bone marrow
(B6C3F1)
Subcutaneous, 0, 2,500,
5,000 mg/kg
Single dose
Negative at all doses
Allen et al, (1990)
High
Sister chromatid
exchange
Mouse lung cells and
peripheral lymphocytes
(B6C3F1)
Inhalation 6 hr/d, 5
d/wk,
0, 4,000, 8,000 ppm
2 wks
Positive at 4,000 and 8,000 ppm
- mouse lung cells; at 8,000 ppm
- peripheral lymph.
Allen et al, (1990)
High
Sister chromatid
exchange
Mouse lung cells
(B6C3F1)
Inhalation 6 hr/d, 5
d/wk,
0, 2,000 ppm
12 wks
Positive at 2,000 ppm
Allen et al, (1990)
High
DNA synthesis
Mouse liver (B6C3F1)
Gavage, 1,000 mg/kg;
inhalation, 4,000 ppm
Single dose;
2 hrs
Negative in both oral and
inhalation studies
Lefevre and Ashbv (1989)
High
Unscheduled DNA
synthesis
Mouse hepatocytes
(B6C3F1)
Inhalation, 2,000 and
4,000 ppm.
2 or 6 hrs
Negative
Trueman and Ashbv (1987)
Medium
Source: U.S. EPA ( ), Table 4-23, pp. 115-116
50
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4.6 Results from in vivo Genotoxicity Assays of Dichloromethane in Rats and Hamsters
Asssiy
Test System
Route :iiul Dose
Dm ml ion
Results
Reference
D:it;i Qiiiility
K\ iiliiiition
DNA SSBs by alkaline
elution
Rat hepatocytes
Inhalation, 3 or 6 hrs,
2,000 and 4,000 ppm
3 or 6 hrs
Negative at all concentrations
and time points
Graves et al, (1994b)
Medium
DNA SSBs by alkaline
elution
Rat liver homogenate
Gavage, 2 doses, 425
mg/kg and 1,275 mg/kg,
administered 4 and 21
hrs before liver
harvesting
4 or 21 hrs (time
between dosing
and liver
harvesting)
Positive at 1,275 mg/kg
Kitchin and Brown f 1989)
High
DNA SSBs by alkaline
elution
Rat liver and lung
homogenate
Liver: inhalation, 4,000,
5,000 ppm
Lung: inhalation, 4,000
ppm
3 hrs
3 hrs
Negative for both liver and
lung at all concentrations
Graves et al, (1995)
High
DNA adducts
Rat liver and kidney cells
Intraperitoneal, 5 mg/kg
Single dose
Negative
Watanabe et al. (2007)
Medium
DNA-protein cross-
links
Hamster liver and lung
cells
Inhalation, 6 hr/d, 500,
1,500, 4,000 ppm
3 d
Negative at all concentrations
Casanova et al, (1996)
High
Unscheduled DNA
synthesis
Rat hepatocytes
Gavage, 100, 500,1,000
mg/kg
Liver harvested 4
and 12 hrs after
dosing
Negative 4 or 12 hrs after
dosing
Trueman and Ashbv (1987)
Medium
Unscheduled DNA
synthesis
Rat hepatocytes
Inhalation, 2 or 6 hrs,
2,000 and 4,000 ppm
2 or 6 hrs
Negative at both
concentrations and exposure
durations
Trueman and Ashbv (1987)
Medium
Unscheduled DNA
synthesis
Rat hepatocytes
Intraperitoneal, single
dose, 400 mg/kg
Single dose
Negative 48 hrs after dosing
Mirsalis et al, (1989)
High
Source: U.S. EPA ( ), Table 4-24, p. 120
51
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5 References
Also. S; Take. M; Kasai < v en oh. H; Umedn . Matsumoto. M; Fukushima. S. (2014). Inhalation carcinogenicity of
dichloromethane in rats and mice. Inhal Toxicol 26: 435-451.
https://heronet.epa.eov/heronet/index.cfm/reference/download/referer
Allen. J; Kligerman \ t ampbell. J; Westbrook-Collins. B: Erexson. G; Kan i >-'iger. E. (1990). Cytogenetic analyses of mice
exposed to dichloromethane. Environ Mol Mutagen 15: 221-228. http://dx.doi.org/10.1002/em.28501504Q9
yi. C; O'Shea. WJ; Graham. J A; Miller. FJ. (1986). The effects of inhalation of organic chemical air contaminants on murine lung
host defenses. Fundam Appl Toxicol 6: 713-720. http://dx.doi.org/10.1016/0272-0590(86)90184-3
Barry. KH; Zhang. Y; Lan. Q; Zahm. SH; Holford. TR; Leadenn •!% le. P; Hosgood. HP: Chanock. S: Yeager. M; Rothman. N:
Zheng. T. (201 1). Genetic variation in metabolic genes, occupational solvent exposure, and risk of non-hodgkin lymphoma.
Am J Epidemiol 173: 404-413.
Bell. BP: Franks. P; Hildreth. N: Melius. J. (1991). Methylene chloride exposure and birthweight in Monroe County, New York.
Environ Res 55: 31-39.
Brender. ID: Shinde. Ml ltv.» ^ r ng. X: Langlois. PH. (2014). Maternal residential proximity to chlorinated solvent emissions
and birth defects in offspring: a case-control study. Environ Health 13: 96. http://dx.doi.org 10 I I \ \ \ 0 ;s \ \ '- -96
Burek. ID: Nitschke. KD: Bell. TJ: Wackerle. PL: Childs. RC: Beyer. IE: Ditten py. LW: McKenna. Ml. (1984).
Methylene chloride: A two-year inhalation toxicity and oncogenicity study in rats and hamsters. Fundam Appl Toxicol 4: 30-
47. http://dx.doi.org/10.1093/toxsci/4.1.30
Calle If. CR: Philpot. RM. (1980). Cytochrome P-450 mediated genetic activity and cytotoxicity of seven halogenated
aliphatic hydrocarbons in Saccharomyces cerevisiae. Mutat Res 77: 55-63. http://dx.doi.org 10 101 01 I.IS- 80)(s01 JO J
Cantor. KP: Ste ton. LA: Posemeci. M. (1995). Occupational exposures and female breast cancer mortality in the United
States. J Occup Environ Med 37: 336-348.
Carton. M: Barul. C: Menviell' i w O Sanchez. M: Pilorget. i M ticket L i Group. IS. (2017). Occupational
exposure to solvents and risk of head and neck cancer in women: a population-based case-control study in France. BMJ Open
7:e012833.
Casanova. M: B eck. H. (1997). Dichloromethane metabolism to fomialdehyde and reaction of formaldehyde with nucleic
acids in hepatocytes of rodents and humans with and without glutathione S-transferase T1 and Ml genes. Fundam Appl
Toxicol 37: 168-180. http://dx.doi.orj toxsci/37.2.168
Casanova. M: Cone eck. H. (1996). DNA-protein cross-links (DPX) and cell proliferation in B6C3F1 mice but not Syrian
golden hamsters exposed to dichloromethane: Pharmacokinetics and risk assessment with DPX as dosimeter. Fundam Appl
Toxicol 31: 103-116. http://dx.doi.orj 06/faat. 1996.0081
52
-------
Casanova. M; Devo. DF; Heck. H. (1992). Dichloromethane (methylene chloride): metabolism to formaldehyde and formation of
DNA-protein cross-links in B6C3F1 mice and Syrian golden hamsters [Letter], Toxicol Appl Pharmacol 114: 162-165.
http://dx.doi.on )041-008X(92)90109-6
Chaigne. r% 1 jsfargue? Marie. I; Huttenbera^i r% Ui >v iia C; Marchand-Adam. S: Maillot I', Oiot. E. (2015). Primary Sjogren's
syndrome and occupational risk factors: A case-control study. J Autoimmun 60: 80-85.
Christensen. KY; Vizcava. D; Richardson. H; Lavoi son. K; Siemiatvcki. J. (2013). Risk of selected cancers due to
occupational exposure to chlorinated solvents in a case-control study in Montreal. J Occup Environ Med 55: 198-208.
Cocco. P; Heineman. EF; Dosemeci. M. (1999). Occupational risk factors for cancer of the central nervous system (CNS) among US
women. Am J Ind Med 36: 70-74.
Costantim V r^'nvenuti. \ \ meis. P; Kriebel 1 amino. R; Ramazzotti. V: Rodella. S: Stagnaro. E; Crosignani. P; Amadori. D;
Mirabelli. D: Sommani 1 . Holletn t < loschel. L; Romeo. L; Miceti. (3: Tozzi. G; Men o ^ \Iiltoni. S: Mili^ i 1 (2008).
Risk of leukemia and multiple myeloma associated with exposure to benzene and other organic solvents: Evidence from the
Italian Multicenter Case-control study. Am J Ind Med 51: 803-811.
Crebelli. R; Benigni. R; Franekic. J; Conn \ onti. L; Car ere. A. (1988). Induction of chromosome malsegregation by halogenated
organic solvents in Aspergillus nidulans: Unspeciftc or specific mechanism? MutatRes 201: 401-411.
http://dx.doi.on 10 101 00. -10 *88)900.
Demarini. DM; Shelton. ML; Warren. SH; Ross. TM; Shirr Lichard. AM; Pegram. RA. (1997). Glutathione S-transferase-
mediated induction of GC->AT transitions by halomethanes in Salmonella. Environ Mol Mutagen 30: 440-447.
http://dx.doi.on 02/fSICI)l 098-2280(1997)30:4<440::AID-EM9>3.0.CQ:2-M
Devereir, < U t > \ * M; Parry. JM. (1996). An investigation into the activation and deactivation of chlorinated
hydrocarbons to genotoxins in metabolically competent human cells. Mutagenesis 11: 247-274.
http://dx.doi.on 10 1093/mutage/ II '< J I
Dosemeci. M; Cocco. P; Chow. WH. (1999). Gender differences in risk of renal cell carcinoma and occupational exposures to
chlorinated aliphatic hydrocarbons. Am J Ind Med 36: 54-59.
Dow Chem Co. (1988). INITIAL SUBMISSION: EVALUATION OF THE ACUTE NEUROPHARM ACOLOGIC EFFECTS OF
DICHLOROMETHANE IN RATS (FINAL REPORT) WITH ATTACHMENTS AND COVER LETTER DATED 050792.
(OTS: OTS0537278; 8EHQ Num: 8EHQ-0592-3826; DCN: 88-920002468; TSCATS RefID: 423282; CIS: NA).
53
-------
Garcia. E; Hurley. S; Nelson. DO; Hertz. A; Reynolds. P. (2015). Hazardous air pollutants and breast cancer risk in California
teachers: a cohort study. Environ Health 14: 14.
General Elet k (1976a). Dichloromethane fourteen day range finding study in dogs. (OTS: OTS0205887; 8EHQ Num: NA;
DCN: 878210708; TSCATS RefID: 16715; CIS: NA).
General Elet L (1976b). DICHLOROMETHANE FOURTEEN DAY RANGE FINDING STUDY IN RATS. (OTS:
OTS0205887; 8EHQNum: NA; DCN: 878210707; TSCATS RefID: 16714; CIS: NA).
General Elet L (1990). MORBIDITY STUDY OF OCCUPATIONAL EXPOSURE TO METHYLENE CHLORIDE USING A
COMPUTERIZED SURVEILLANCE SYSTEM (FINAL REPORT) WITH COVER SHEETS AND LETTER DATED
041190. (OTS: OTS0522984; 8EHQ Num: NA; DCN: 86-900000421; TSCATS RefID: 406678; CIS: NA).
General Electric Company. (1976). Dichloromethane: Reproduction and ninety day oral toxicity study in rats. (878210710).
Mattawan, MI: International Research and Development Corporation.
Gibbs. GW. (1992). SUPPLEMENT: MORTALITY OR WORKERS EMPLOYED AT A CELLULOSE ACETATE &
TRIACETATE FIBERS PLANT IN CUMBERLAND, MD (FINAL REPORT) WITH COVER LETTER DATED 061792.
(OTS: OTS0516635-3; 8EHQNum: 8EHQ-0692-0772; DCN: 89-920000119; TSCATS RefID: 427311; CIS: NA).
Gibbs. GW; Amsel. J; Soden. K. (1996). A cohort mortality study of cellulose triacetate-fiber workers exposed to methylene chloride.
J Occup Environ Med 38: 693-697.
Gocke. E; King. MT; Eckhardt. K; Wild. P. (198 1). [Mutagenicity of cosmetics ingredients licensed by the European communities].
MutatRes 90: 91-109. http://dx.doi.oiv 10 101 > 01 : I. I v s 1)90072-0
Gold. LS; Stewan Milliken. K; Purdue. M; Severson. R; Seix.r 'x r%Uu \ Martge. P; Davis. S; De Roos. A.J. (2010). The
relationship between multiple myeloma and occupational exposure to six chlorinated solvents. Occup Environ Med 68: 391-
399.
Graves. RJ; Callanc . T. (1994a). The role of formaldehyde and S-chloromethylglutathione in the bacterial mutagenicity
of methylene chloride. Mutat Res 320: 235-243. http://dx.doi.ore/ 5/0165-1218(94)90050-7
Graves. RJ; Coutts. C; Eyton-Jones. H; Green. T. (1994b). Relationship between hepatic DNA damage and methylene chloride-
induced hepatocarcinogenicity in B6C3F1 mice. Carcinogenesis 15: 991 -996. http://dx.doi.ore/10 lO'O/carciii I ,v!
Graves. RJ; Coi: en. T. (1995). Methylene chloride-induced DNA damage: An interspecies comparison. Carcinogenesis 16:
1919-1926. http://dx.doi.ore/10.1093/carcin/
Gravi en. T. (1996). Mouse liver glutathione S-transferase mediated metabolism of methylene chloride to a mutagen in the
CHO/HPRT assay. Mutat Res Genet Toxicol 367: 143-150. http://dx.doi.ore/ >5)00087-9
Gravi em an. P; Jones. S; Green. T. (1996). DNA sequence analysis of methylene chloride-induced HPRT mutations in
Chinese hamster ovary cells: Comparison with the mutation spectrum obtained for 1,2-dibromoethane and formaldehyde.
Mutagenesis 11: 229-233. http://dx.doi.ore/10.1093/mutaee/l 1.3.229
54
-------
Green. T. (1983). The metabolic activation of dichloromethane and chlorofluoromethane in a bacterial mutation assay using
Salmonella typhimurium. Mutat Res Genet Toxicol 118: 227-288. http://dx.doi.Hv 10 101 5/0165-1218(83)90." I I J
Hazleton Laboratories. (1983). 24-month oncogenicity study of methylene chloride in mice: Final report. (45-8303005). New York,
NY: National Coffee Association, https://ntrl.ntis. gov/NTRL/dashboard/searchResults.xhtml?searchQuery=OTSQ5Q56Q6
Hear er. JW. (1999). Mortality study of two overlapping cohorts of photographic film base manufacturing employees
exposed to methylene chloride. J Occup Environ Med 41: 1154-1169.
Hegi. ME; Soderkvist. < JF, Schoonhoven. R; Swenben Ivjii. F; Maronpot. R: Anderson. MW: Wiseman. RW. (1993).
Characterization of p53 mutations in methylene chloride-induced lung tumors from B6C3F1 mice. Carcinogenesis 14: 803-
810. http://dx.doi.ore/10.1093/carcin/ B
Heineman. EF; Cocco. P; Gomez. MR; Dosemeci. M; Stevun Uaye ihro. S 1\ 1 boma h 1 i>r. A. (1994).
Occupational exposure to chlorinated aliphatic hydrocarbons and risk of astrocytic brain cancer. Am J Ind Med 26: 155-169.
Hirati 1'. ('ho. YM; Toyotlt I \l jgi, J I: Suzuki. I; Nishikavu \ « 1 ..>va- K. (2016). Lack of in vivo mutagenicity of 1,2-
dichloropropane and dichloromethane in the livers of gpt delta rats administered singly or in combination. J Appl Toxicol 37:
683-691. http://dx.doi.org/10.1002/iat.3416
Fiu. Y; Kabter. SL; Tennani \U < own send. A J; Kligerman (2006). Induction of DNA-protein crosslinks by dichloromethane in
a V79 cell line transfected with the murine glutathione-S-transferase theta 1 gene. Mutat Res Genet Toxicol Environ Mutagen
607: 231-239. http://dx.doi.on 10 101 i.mrgentox.200 0l0l'<
Infante-Rivai1 Siemiatvcki < 1 Ahani. R; Nadon. L. (2005). Maternal exposure to occupational solvents and childhood leukemia.
Environ Health Perspect 113: 787-792.
J on gen. W1V ik. GM; Koeman. JH. (1978). Mutagenic effect of dichloromethane on Salmonella typhimurium. Mutat Res-
Fundam Mol Mech Mutagen 56: 245-248. http://dx.doi.org 10 101 0*-L h1 < ^ );»0 i'M S
Jongen. WMF; Harm sen. EGM; Alink. GM; Koeman. JH. (1982). The effect of glutathione conjugation and microsomal oxidation on
the mutagenicity of dichloromethane in S. typhimurium. Mutat Res-Fundam Mol Mech Mutagen 95: 183-189.
http://dx.doi.on *82)90256-1
Jongen. WMF, 1 oliman. PHM; Kottenhagen. MJ; Alink. GM. Hcrendt I Ivpeman. JH. (1981). Mutagenicity testing of
dichloromethane in short-term mammalian test systems. Mutat Res-Fundam Mol Mech Mutagen 81: 203-213.
http://dx.doi.on )027-5107(81)90035-X
Kalkbrenner. AE; Daniels. JL; Chen. JC; Poole. C; Emch. M; Morrissev. J. (2010). Perinatal exposure to hazardous air pollutants and
autism spectrum disorders at age 8. Epidemiology 21: 631-641.
Kavser. Ml', \ uilleumln c. (2001). Dehalogenation of dichloromethane by dichloromethane dehalogenase/glutathione S-transferase
leads to formation of DNA adducts. J Bacteriol 183: 5209-5212.
Khudolev. VV; Mizgireuv. I; Pliss. GB. (1987). The study of mutagenic activity of carcinogens and other chemical agents with
Salmonella typhimurium assays: Testing of 126 compounds. Arch Geschwulstforsch 57: 453-462.
55
-------
Kirschm; >wn. NM; Coots. RH; Morgareidge. K. (1986). Review of investigations of dichloromethane metabolism and
subchronic oral toxicity as the basis for the design of chronic oral studies in rats and mice. Food Chem Toxicol 24: 943-949.
http://dx.doi.org/ i 0 J 0 i 6/0278-6915(86)90322-4
Kitch 111 i i r%iowri ,11 (1989). Biochemical effects of three carcinogenic chlorinated methanes in rat liver. T eratog Carcinog
Mutagen 9: 61-69. http://dx.doi.org/10.1002/tcm.17700901Q8
Kramers. PGN: Mont H.CA; Bissumbhar. B; Mulder. CR. (1991). Inhalation exposure in Drosophila mutagenesis assays: Experiments
with aliphatic halogenated hydrocarbons, with emphasis on the genetic activity profile of 1,2-dichloroethane. Mutat Res 252:
17-33. http://dx.doi.ore 10 101 01 : i i h'M)90248~7
Kumagai. S: Sobue. T; Makiuchi. T; Kubo. S: Uehara. S: Havashi. T; Sato. KK; En do. G. (2016). Relationship between cumulative
exposure to 1,2-dichloropropane and incidence risk of cholangiocarcinoma among offset printing workers. Occup Environ
Med 73: 545-552.
Landi. S: Naccarati. A; Ross. MK; Hanlev. NM; Dailev. L; Devlin luez. M; Pegram. RA; DeMarini. DM. (2003). Induction
of DNA strand breaks by trihalomethanes in primary human lung epithelial cells. Mutat Res Genet Toxicol Environ Mutagen
538: 41-50. http://dx.doi.oiv 10 101 / l'>\; ¦> is.03)0008 \
Lanes. SF; Cohen. A; Rothman. KJ; Drever. NA; Soden. KJ. (1990). Mortality of cellulose fiber production workers. Scand J Work
Environ Health 16: 247-251.
Lanes. SF; Rothman. KJ; Drever. NA; Soden. KJ. (1993). Mortality update of cellulose fiber production workers. Scand J Work
Environ Health 19: 426-428.
Lash. er. CE; So. Y; Shore. M. (1991). Neurotoxic effects of methylene chloride: Are they long lasting in humans? Occup
Environ Med 48: 418-426.
Lete\ ;hby. J. (1989). Evaluation of dichloromethane as an inducer of DNA synthesis in the B6C3F1. mouse liver.
Carcinogenesis 10: 1067-1072. http://dx.doi.org/10.1093/carcin/10.6.1067
Maltoni. C; Cot! erino. G (1988). Long-term carcinogenicity bioassays on methylene chloride administered by ingestions to
Sprague-Dawley rats and Swiss mice and by inhalation to Sprague-Dawley rats. Ann N Y Acad Sci 534: 352-366.
http://dx.doi.ore 10 I I I I i I r >. r88.tb30122.x
Mars b \ rn)tta. S; Martin. MY; Mccormick. WA; Guengerich l'P (2004). Formation and mass spectrometric analysis of DNA
and nucleoside adducts by S-(l-acetoxymethyl)glutathione and by glutathione S-transferase-mediated activation of
dihalomethanes. Chem Res Toxicol 17: 45-54. http://dx.doi.org/10.1021 /tx034156z
Mattei. F; Guida. F; Matrat. M; Cenee. S; Cyr. D; Sanchez. M; Radoi. L; Menvielle. G; Jellouli I 1 jrton. M; Bara. S; Marrer. E;
Luce. D; S tucker. 1. (2014). Exposure to chlorinated solvents and lung cancer: results of the ICARE study. Occup Environ Med
71: 681-689.
56
-------
Mennear. JH; McConnell. EE; Huff. IE; Retroe. RA; Giddens. E. (1988). Inhalation toxicology and carcinogenesis studies of
methylene chloride (dichloromethane) in F344/N rats and B6C3F1 mice. Ann N Y Acad Sci 534: 343-351.
http://dx.doi.on 10 I I I I j I r )632.1988.tb30121.x
Miligi. L; Costantini. AS; Benvenuti. A; Kriebel I* r%oleiack. V; Tumino K Kamazzoln \ Sella. S; Stagnaro. E; Crosignani. P;
Amadori. D; Mirabelli. D; Sommani. L; Bell schel. L; Romeo. L; Miceli. G; Tozzi. GA; Mendico. I; Vineis. P.
(2006). Occupational exposure to solvents and the risk of lymphomas. Epidemiology 17: 552-561.
MitiKil-i S, 1'oisuka \ , Suzuki. Y; Nakai 1 oto. M; Koiima. M; Arakawa. H; Takemura. S; Tanaka. S; Mambashi. S; Kinoshita.
M; Matsuda. T; Shibata 1 . Niakagama. H; Ochim \ iviibo. S; Nakamori. S; Esumi. H; Tsuchihara. K. (2016). Hypermutation
and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes.
Carcinogenesis 37: 817-826. http://dx.doi.org/10.1093/carcin/bgw066
Mirsalis. 1 \ son. CK; Steinmei t 1 1 <»h. EK; Hamilton. CM; Bakke. IP; Spalding. JW. (1989). Measurement of unscheduled
DNA synthesis and S-phase synthesis in rodent hepatocytes following in vivo treatment: Testing of 24 compounds. Environ
Mol Mutagen 14: 155-164. http://dx.doi.org/ 2/em.2850140305
Moral es - Suarez-Varela. MM, Olsen. J; Villeneuve. S; Johansen. P; Kaerlev. L; Llopis-Gon: \ NVingren t \ jdell. L; Ahrens.
W; Stang. A; Merletti. F; Gorini. G; Aurrekoetx-' t << i ^ ! i u U uenel. P. (2013). Occupational exposure to
chlorinated and petroleum solvents and mycosis fungoides. J Occup Environ Med 55: 924-931.
Moser. VC; Cheek. BM; Macphail. RC. (1995). A multidisciplinary approach to toxicological screening: III. Neurobehavioral toxicity.
J Toxicol Environ Health A 45: 173-210. http://dx.doi.oiy 10 iOSO 1-3 -0V: i^s8
Narotsky. MG; Kavlock. RJ. (1995). A multidisciplinary approach to toxicological screening: II. Developmental toxicity. J Toxicol
Environ Health 45: 145-171. http://dx.doi.org/10.1080/15287399509531987
Neta. G; Ste tram an. P; Hein. Ml; Waters. MA; Purdue. MP; Samanic. C; Cob et. MS; In skip. PP. (2012).
Occupational exposure to chlorinated solvents and risks of glioma and meningioma in adults. Occup Environ Med 69: 793-
801.
Nitschke. KD; Bure iba. RJ; Rampy. LW; McKenna. MI. (1988). Methylene chloride: A 2-year inhalation toxicity
and oncogenicity study in rats. Fundam Appl Toxicol 11: 48-59. http://dx.doi.oo 3272-0590(88)90269-2
NTP. (1986). NTP Toxicology and Carcinogenesis Studies of Pichloromethane (Methylene Chloride) (CAS No. 75-09-2) in F344/N
Rats andB6C3Fl Mice (Inhalation Studies). 306: 1-208.
Olvera-Bello. AE; Estrada-Mum < < hzonu a. (2010). Susceptibility to the cytogenetic effects of dichloromethane is
related to the glutathione S-transferase theta phenotype. Toxicol Lett 199: 218-224.
http://dx.doi.org/10.1016/i.toxlet.l010 0's 002,
Ott. h i v L»n\ I i Uolder. BB; Bronson. JM; Williams. PR. (1983). Health evaluation of employees occupationally exposed to
methylene chloride: Clinical laboratory evaluation. Scand J Work Environ Health 9(1): 17-25.
57
-------
Peeraro. RA; Andersen. ME; Warren. SH; Ross. TM; Claxton. LP. (1997). Glutathione S-transferase-mediated mutagenicity of
trihalomethanes in Salmonella typhimurium: Contrasting results with bromodichloromethane off chloroform. Toxicol Appl
Pharmacol 144: 183-188. http://dx.doi.ore/10.1006/taap. 1997.8123
Purdue. MP; Stewai i I uosen. MC; Colt. IS; Locke. SI; Hein. Ml; Waters. IS I \ lauknxl HI. Davis. F; Ruterbusch. J; Schwartz.
K; Chow. WH; Rothman. N; Hofmann. IN. (2016). Occupational exposure to chlorinated solvents and kidney cancer: a case-
control study. Occup Environ Med 74: 268-274.
Radican. < KLdr. A; Stew\m i1 Wartenberg. D. (2008). Mortality of aircraft maintenance workers exposed to trichloroethylene and
other hydrocarbons and chemicals: Extended follow-up. J Occup Environ Med 50: 1306-1319.
S 'l1' ^ ^ • >so. M. 1'olen. T; Greening. M. (1988). Evaluation of in vivo mutagenicity of low-dose methylene chloride in mice. Int J
Toxicol 7: 699-703. http://dx.doi.org/10.3109/10915818809019544
Roberts. AL; Lyall. K; Hart. IE; Laden t ^ V \ \ ^ k. »enen. KC; Ascherio. A; Weisskopf. Mu (2013). Perinatal Air
Pollutant Exposures and Autism Spectrum Disorder in the Children of Nurses' Health Study II Participants. Environ Health
Perspect 121: 978-984.
Rodrigut tiz. R. (1998). Biotransformation of several structurally related 2B compounds to reactive metabolites in the somatic
w/w+ assay of Drosophila melanogaster. Environ Mol Mutagen 31: 390-401. http://dx.dou 2/(SICD1098-
2280(1998)31:4<390::AID-EM12>3.0.CQ:2-7
Roldan-Ariona. T; Puevo. C. (1993). Mutagenic and lethal effects of halogenated methanes in the Ara test of Salmonella typhimurium:
Quantitative relationship with chemical reactivity. Mutagenesis 8: 127-131. http://dx.doi.Org/10.1093/miitage/8:2.127
Ruder. AM; Yiin. JH; Waters. MA; Carreon. T; Hein. MI; Butler. M \ 1 atvert. GM; Davis-Kit^ I oeg. E; Elsnci t i, Nietn1 \ ;ker. N. (2007). Solvent exposure and malignant
lymphoma: A population-based case-control study in Germany. J Occup Med Toxicol 2: 2.
Serota. DG; Thakui \lv 1 lUm! KM; Kirschman. JC; Brown. NM; Coots. RH; Morgareidge. K. (1986a). A two-year drinking-water
study of dichloromethane in rodents: I. Rats. Food Chem Toxicol 24: 951-958. http://dx.doi.org/10.1016/0278-6915(86)90323-
6
Serota. DG; Thakui \lv 1 lUin! KM; Kirschman. JC; Brown. NM; Coots. RH; Morgareidge. K. (1986b). A two-year drinking-water
study of dichloromethane in rodents: II. Mice. Food Chem Toxicol 24: 959-963. http://dx.doi.org/' >/0278~
6915(86)90324-8
58
-------
Sheldon. T; Richardson. CR: Elite ^ (1987). Inactivity of methylene chloride in the mouse bone marrow micronucleus assay.
Mutagenesis 2: 57-59.
Shell Oil. (1986). TEN DAY INHALATION TOXICITY STUDY TO INVESTIGATE THE EFFECTS ON RAT AND MOUSE
LIVER AND LUNG WITH METHYLENE CHLORIDE. (OTS: OTS0514365; 8EHQ Num: NA; DCN: 86-880000287;
TSCATS RefID: 305688; CIS: NA). Shell Oil Co.
Siemiatvcki. J. . (1991). Risk factors for cancer in the workplace. In J Siemiatycki (Ed.). Boca Raton, FL: CRC Press.
Silver. SK; Pinkerton. LE; Flemin es. J.H; Allee. S; Luo. L; Bertke. SJ. (2014). Retrospective Cohort Study of a
Microelectronics and Business Machine Facility. Am J Ind Med 57: 412-424.
Soden. KJ. (1993). An evaluation of chronic methylene chloride exposure. J Occup Med 35: 282-286.
Suzuki. T; Yanagiba. Y; Suda. M; Wane. RS (2014). Assessment of the genotoxicity of 1,2-dichloropropane and dichloromethane
after individual and co-exposure by inhalation in mice. J Occup Health 56: 205-214.
Talbc Marshall. LP; Raeer. JR; Arena. VC; Sharma. RK; Stacy. SL. (2015). Air toxics and the risk of autism spectrum disorder:
the results of a population based case-control study in southwestern Pennsylvania. Environ Health 14: 80.
Talibov. M; Lehtinen-Jacks. S; Martinser aerheiro. K; Lynge. E; Sparen. P; Trveevadottir. L; Weiderpass. E; Kauppinen. T;
Kyyronen. P; Pukkala. E. (2014). Occupational exposure to solvents and acute myeloid leukemia: a population-based, case-
control study in four Nordic countries. Scand J Work Environ Health 40: 511-517.
Taskinen. H; Lindbohm. ML; Hemminki. K (1986). Spontaneous abortions among women working in the pharmaceutical industry. Br
J Ind Med 43: 199-205.
Thier. R; Taylot ^emble. SE; Humphreys. WG; Persmark. M; Kettenn M Gueneerich. FP. (1993). Expression of mammalian
glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to
dihalomethanes. Proc Natl Acad Sci USA 90: 8576-8580.
Thilagar. AK; Kumaroo. V. (1983). Induction of chromosome damage by methylene chloride in CHO cells. DNA Repair 1 16: 361 -
367. http://dx.doi.oi y 10 101 /0165-1218f831900 I
Tom en son. J A. (201 1). Update of a cohort mortality study of workers exposed to methylene chloride employed at a plant producing
cellulose triacetate film base. Int Arch Occup Environ Health 84: 889-897.
Trueman. RW; Ash by. J (1987). Lack of UDS activity in the livers of mice and rats exposed to dichloromethane. Environ Mol
Mutagen 10: 189-195. http://dx.doi.ore/10.1002/em.2850100209
(2011). Toxicological review of dichloromethane (methylene chloride) (CASRN 75-09-2): In support of summary
information on the Integrated Risk Information System (IRIS) [EPA Report], (EPA/635/R-10/003F). Washington, D.C.
https://cfpub.epa.gov/ncea/iris/iris documents/documents/toxreviews/0070tr.pdf
Vizcava. D; Christensen. KY; Layout miatveki. J. (2013). Risk of lung cancer associated with six types of chlorinated solvents:
results from two case-control studies in Montreal, Canada. Occup Environ Med 70: 81-85.
59
-------
von Ehrenstein. OS; Aralis. H; Cockburn. M; Ri (2014). In Utero Exposure to Toxic Air Pollutants and Risk of Childhood
Autism. Epidemiology 25: 851-858.
Wang. R; Zhang. Y; Lan. Q; Holford. TR; Leaderer. .thm. SH; Boyle. P; Dosemeci. M; Rothman. N: Zhu \ » Mn. Q; Zheng. T.
(2009). Occupational exposure to solvents and risk of non-Hodgkin lymphoma in Connecticut women. Am J Epidemiol 169:
176-185.
Warbrick. EV; Kilgour. JD; Dearman. RJ; Kimber. I; Dugard. PH. (2003). Inhalation exposure to methylene chloride does not induce
systemic immunotoxicity in rats. J Toxicol Environ Health A 66: 1207-1219. http://dx.doi.oi ^ 10 10 V l . * 73 9 0 3 0 64 1 0
Watanabe. K; Liberman. RG: Skipper. PL; Tannenbaum. SR; Guengerich (2007). Analysis of DNA adducts formed in vivo in rats
and mice from 1,2-dibromoethane, 1,2-dichloroethane, dibromomethane, and dichloromethane using HPLC/accelerator mass
spectrometry and relevance to risk estimates. Chem Res Toxicol 20: 1594-1600. http://dx.doi.org/10.1021/tx700125p
Westbrook-Collins. en. JW; Sharief. Y; Campbell. J. (1990). Further evidence that dichloromethane does not induce
chromosome damage. J Appl Toxicol 10: 79-81. http://dx.doij 2/iat.2550100203
Windham. GC; Zha Gunier. R; Croen. LA; Grether. IK. (2006). Autism spectrum disorders in relation to distribution of
hazardous air pollutants in the San Francisco Bay area. Environ Health Perspect 114: 1438-1444.
Yang t bang. J; Chu. W; Yin O, 1'cinpleton. MR. (2014). Haloactamides versus halomethanes formation and toxicity in
chloraminated drinking water. J Hazard Mater 274: 156-163. http://dx.doi.org/10.1016/i .jhazmat.201 I 0 I 00 S
Zeiger. E. (1990). Mutagenicity of 42 chemicals in Salmonella. Environ Mol Mutagen 16: 32-54.
http://dx.doi.org/10.1002/em.2850160504
Zeliezic. D; Mladinic. M; Kopjar. N; Radulovic. AH. (2016). Evaluation of genome damage in subjects occupationally exposed to
possible carcinogens. Toxicol Ind Health 32: 1570-1580. http://dx.doi.on )748233714568478
60
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