r
TECHNICAL REPORT DATA
(fttste rtmd I/utnictions on the revent be fort completuifj
1. REPORT NO.
hPA/60Q/8-88/024
3. RECIPIENT'S ACCESSION NO.
PB88-179932/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for Chloromethane
6. REPORT DATE
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME ANO ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO ADDRESS
13. TYPE OF REPORT ANO PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
is. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD5 or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS ANO DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Croup
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (This Report)
Unclassified
21. NO. Of PAGES
20. SECURITY CLASS fThis page)
Unclassified
22. PRICE
EPA Perm 2220-1 (R*v. 4-77) PREVIOUS KOITIOM IS OBSOLCTK
-------
EPA/600/8-88/024
February, 1987
HEALTH EFFECTS ASSESSMENT
FOR CHLOROHETHANE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
-------
DISCLAIMER
This document has been reviewed 1n accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
-------
PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with chloro-
methane. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary reflecting
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases.
The basic literature searched supporting this document Is current up to
June, 1986. Secondary sources of Information have also been relied upon In
the preparation of th.1s report and represent large scale health assessment
efforts that entail extensive peer and Agency review. The following Office
of Health and Environmental Assessment (OHEA) sources have been extensively
utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Halomethanes. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-051. NTIS PB81-117624.
U.S. EPA. 1982. Errata for Ambient Water Quality Criteria
Document for Halomethanes. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC.
U.S. EPA. 1983. Reportable Quantity Document for Methyl Chloride.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response. Washington, DC.
U.S. EPA. 1986a. Health and Environmental Effects Profile for
Methyl Chloride. Prepared by the Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency
Response, Washington, DC.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD<; (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
111
-------
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFO$. estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$i) and oral (RfD$g)
exposures.
The RfD (formerly AIC) Is similar 1n concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfO Is route-specific and estimates acceptable exposure for either oral
(RfDn,) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained In U.S.
EPA (1984).
For compounds for which there 1s sufficient evidence of cardnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-]*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
-------
ABSTRACT
In order to place the risk assessment evaluation In proper context,.
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
Exposure to chloromethane vapor has been shown to Increase the Incidence
of kidney tumors In male B6C3F1 mice (CUT, 1981; NIOSH, 1984). No other
studies regarding the carcinogenic potential of chloromethane by other
routes were available. Because of the lack of data, U.S. EPA (1986a)
calculated an oral q-j* from the Inhalation data. This value, 1.26xlO~2
(mg/kg/day)"1 Is also presented In this document. An Inhalation q-]*,
also calculated from the CUT (1981) study, was determined to be 6.23xlO~3
(mg/kg/day)"1. Chloromethane has been classified by the U.S. EPA (1986a)
as a Group C carcinogen.
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
-------
TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC .
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral. .
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. HEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDc)
6.2. REFERENCE DOSE (RfD)
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral
6.3.2. Inhalation
REFERENCES
APPENDIX
Page
. . . 1
. . . 3
. . . 3
. . . 3
. . . 5
. . . 5
. . . 5
. . . 5
. . . 6
. . . 6
. . . 6
. . . 9
. . . 9
. . . 9
. . . 13
. . . 15
. . . 15
15
. . . 15
15
. . . 17
17
. . . 19
20
. . . 20
. . . 20
. , , 20
. . . 20
. . . 20
. . . 22
. . . 29
V11
-------
LIST OF TABLES
No. Title Page
1-1 Selected Chemical and Physical Properties of Chloromethane. . 2
4-1 Numbers of Male Mice Sacrificed or Dying and Kidney Tumor
Prevalence 1n Months 13-24 16
4-2 Carcinogenic Potency of Chloromethane {99.99% pure) 1n Male
B6C3F1 Mice Exposed by Inhalation 6 Hours/Day, 5 Days/Week. . 18
6-1 Derivation of a q-|* for Inhalation Exposure 21
-------
LIST OF ABBREVIATIONS
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
EEG Electroencephalogram
ppm Parts per million
RfO Reference dose
RfD$ Subchronlc reference dose
SCE S1ster-chromat1d exchange
SGPT Serum glutamlc pyruvlc transamlnase
STEL Short-term exposed level
TLV Threshold limit value
1x
-------
1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and half-lives of chloro-
methane (CAS No. 74-87-3) are presented 1n Table 1-1.
The sources of atmospheric chloromethane are both natural and anthropo-
genic. Chloromethane 1s always present 1n the atmosphere at low concentra-
tions, depending upon seasonal, diurnal and latitudinal variations (KhalU
and Rasmussen, 1983; Singh et al., 1982). Reaction with HO radical Is the
most significant process for removal of chloromethane from the troposphere
(Davis et al., 1982). Based on an estimated atmospheric half-life of -1
year (Davis et al., 1976) and the lifetime for tropospherlc to stratospheric
transfer of 30 years (DllUng, 1982), ~3X of tropospherlc chloromethane 1s
expected to be transferred to the stratosphere where 1t may participate In
the destruction of the ozone layer (Dining, 1982). Volatilization from
water 1s expected to be the dominant removal mechanism for aquatic chloro-
methane. Based on a recommended value for Henry.1 s Law constant of
9.4xlO"3 atm-mVmol at 25°C (Mackay and Shu1, 1981), the volatilization
half-life from a depth of 1 m was calculated to be 3.8 hours by the method
of Lyman et al. (1982). Based on the fate of chloromethane In water, 1t Is
speculated that volatilization 1s the most Important removal mechanism from
soil. Because of Its low soil adsorption coefficient and relatively high
water solubility, leaching of chloromethane from soil to groundwater may
occur from dumps Hes.
0070h -1- 11/17/86
-------
TABLE 1-1
Selected Chemical and Physical Properties of Chloromethane
Property
Value
Reference
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
Bloconcentratlon factor:
Soil adsorption
coefficient:
Half-lives In
Air:
Water:
chlorinated aliphatic
hydrocarbon
50.49
3.6xlOa mm Hg at 20°C
7.4xl03 mg/l at 20°C
0.91
3 (estimated)
25 (estimated)
-1 year (estimated)
-4 hours (estimated)
rapid flowing shallow
Mackay and Shul, 1981
Mackay and Shul, 1981
Hansch and Leo, 1985
Lyman et al., 1982
Lyman et al., 1982
Davis et al.. 1976
Lyman et al., 1982
0070h
-2-
11/17/86
-------
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Pertinent data regarding absorption of chloromethane following oral
administration could not be located 1n the available literature.
2.2. INHALATION
Putz-Anderson et al. (1981a) exposed men and women to chloromethane at
100 or 200 ppm (207 or 413 mg/m3) for 3 hours. Breath levels of exposed
Individuals reached equilibrium during the first hour. The average breath
level for the eight 100 ppm-exposed Individuals was 36*02 ppm (mean±S.D.).
In the twenty-four 200 ppm-exposed subjects breath concentrations reached
63^23.6 ppm. Breath levels were highly correlated with blood levels (r=0.85
or 0.91, p<0.01) that reached 7.7^6.3 ppm and 11.5*12.3 ppm In the low- and
high-exposure groups, respectively. Rate of absorption or percent absorp-
tion were not estimated In this study.
Nolan et al. (1985) also exposed six male volunteers to 10 or 50 ppm (21
or 103 mg/m3) chloromethane for 6 hours. Blood and expired air concentra-
tions of chloromethane reached equilibrium during the first hour. The
expired air was found to contain 30-70% of the concentration of chloro-
methane In Inhaled air. Absorption rates of 1.4-3.7 pg/m1nute/kg were
calculated using a two-compartment pharmacoklnetlc model.
In a study by Morgan et al. (1970), volunteers Inhaled a known concen-
tration of 38Cl-labeled chloromethane 1n a single breath. The amount of
radioactivity expired In two breaths following breath-holding for 20 seconds
was determined to be 22% of the Inhaled dose. After 1 hour, 29% of the
administered radioactivity was recovered 1n expired air. Therefore, 71-78%
of the 38C1-chloromethane had been retained and potentially absorbed.
0070h -3- 11/17/86
-------
landfy et al. (1983) exposed groups of six male Fischer 344 rats to
chToromethane vapor at 50 or 1000 ppm (103 or 2065 mg/m3) for 6 hours.
Vapor uptake was measured at 1.5 and 2 hours of exposure. At both sampling
times the uptake was 10 yg/m1nute/kg for the 50 ppm exposure level and 165
yg/mlnute/kg for the 1000 ppm exposure level. After 6 hours, the absorbed
dose, calculated using a two-compartment model, was determined to be 3.8
mg/kg for the 50 ppm concentration and 67 mg/kg for the 1000 ppm concen-
tration.
Jn an additional experiment, Landry et al. (1983) exposed male Fischer
344 rats for 6 hours and male beagle dogs for 3 hours to chloromethane vapor
at 50 or 1000 ppm (103 or 2065 mg/m3). Chloromethane levels In the blood
rose rapidly, reached a plateau and were proportional to exposure concentra-
tions. Blood:gas concentration ratios were 1.5 and 1.8 for dogs exposed to
50 or 1000 ppm, respectively, and 1.8 and 1.9 for rats at 50 or 1000 ppm,
respectively.
0070h -4- 11/17/86
-------
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Pertinent data regarding subchronlc effects of chloro-
methane following oral administration could not be located In the available
literature.
3.1.2. Inhalation. In a study by Evtushenko (1966), groups of 10 rats
and 4 rabbits were exposed to either 40 or 240 mg/m3 chloromethane vapor
for 4 hours/day for up to 6 months. Decreased erythrocyte counts and
depletion of lymphold elements 1n the spleen and lymph were observed In rats
at both exposure levels. Disturbed excretory function of the liver was
observed 1n both rats and rabbits at 240 mg/m3. Discoloration of the
optic disc and hlstologlcal lesions of the retina and optic nerve were
observed 1n rabbits at both exposure levels.
Mitchell et al. (1979) exposed groups of 10 male and 10 female Fischer
344 rats (6 weeks old) and 10 male and 10 female B6C3F1 mice (6 weeks old)
to chloromethane vapor at 375, 750 or 1500 ppm (774, 1549 or 3098 mg/m3)
for 6 hours/day, 5 days/week for 13 weeks. Equal numbers of control rats
and mice were observed for food consumption, body weight gain, clinical
signs and mortality. At the end of the exposure period, blood and urine
samples were taken for analysis, ophthalmic examinations were made and the
rats and mice were sacrificed. Treatment-related effects observed 1n the
high-dose groups were as follows: significantly Increased SGPT activity 1n
male mice. Increased relative liver weights In male and female mice and
female rats, hepatic Infarctions In one male mouse and one female rat, and
Increased severity and Incidence of cytoplasmlc vacuollzatlon of hepatocytes
1n male mice. Significantly reduced body weight gain In male and female
rats 1n the 750 and 1500 ppm dose groups was the only other treatment-
related effect observed.
0070h -5- 11/17/86
-------
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding chronic effects of chloromethane
following oral administration could not be located In the available
literature.
3.2.2. Inhalation. Repko and Losley (1979) reviewed the toxic effects of
chloromethane exposure In humans. Without providing dose Information, they
stated that long-term exposure to low levels of chloromethane tends to
result In signs and symptoms confined almost exclusively to the CNS. The
signs and symptoms observed Include headaches, drowsiness, staggering,
muscle weakness, slurred speech, confusion and Impaired judgement.
Repko et al. (1976) conducted an epidemiology study that evaluated the
behavioral and neurological effects of chloromethane 1n humans occupation-
ally exposed to the compound for 1-311 months. Data from 122 exposed and 49
control workers (age 18-61) from several locations were analyzed. Ambient
air concentrations were measured at 1.8-70 ppm (3.7-145 mg/m3) with an
average concentration of 33.57 ppm (69.32 mg/m3). Breath levels of
chloromethane, which ranged from 10.81-24.19 ppm (22.32-49.95 mg/m3), were
significantly correlated with ambient air levels (p<0.005). No significant
differences were observed In the results of neurological examination or EEG
activity. Behavioral tests showed that exposed workers had Impaired per-
formances on time-sharing tasks and Increased magnitudes of finger tremors
compared with controls. These changes correlated with chloromethane levels
1n ambient air and with urine pH, but no relationship between chloromethane
In breath and performance was observed.
In a study by CUT (1981), summarized by NIOSH (1984), groups of 120
male and K'O female Fischer 344 rats and 120 male and 120 female B6C3F1 mice
were exposed to chloromethane vapor at 0, 50, 225 or 1000 ppm (0, 103, 465
0070h -6- 08/06/86
-------
or 2065 mg/m3) for 6 hours/day, 5 days/week for up to 24 months. Interim
sacrifices were performed at 6, 12, 18 and 24 months of exposure. During
the study, rats and mice were observed or evaluated for clinical signs, body
weight gain and mortality. Just before sacrifice, ophthalmologlcal examina-
tions were made, hematologlcal, clinical chemistry and urlnalysls parameters
were determined, and examinations for gross and hlstopathologlcal lesions
were made; neurofunctlon was also examined at 18-24 months. Male and female
mice had Increased mortality at 1000 ppm, while rats were not affected.
Hale mice at 1000 ppm showed a significant (p value not provided) decrease
1n growth rate through the first 18 months of the study. The growth rates
of both male and female rats at 1000 ppm were significantly depressed (p
value not provided) throughout the study. At 18, 21 and 22 months, neuro-
functlonal Impairment was observed 1n most male and female mice exposed to
1000 ppm. The Impairment observed consisted of a positive clutch response
at 18 months and a weakened extensor thrust/scratch response. At 6, 12 and
18 months, male mice at 1000 ppm showed significantly elevated SGPT levels
that were associated with hepatocellular degeneration and necrosis. At 6
and 12 months, female mice at all exposure levels showed significant
Increases 1n SGPT. These Increases were not observed at 18 or 24 months,
and were not associated with liver lesions. Although there were a number of
relative organ weight changes In both rats and mice, they were not consis-
tently related to dose and were bi-directional.
The hlstopathologlcal data (CUT, 1981; NIOSH, 1984) showed a signifi-
cant Increase In the Incidence of hepatic lesions (multlfocal centrllobular
hepatocellular necrosis, karyomegaly, cytomegaly and vacuolar degradation)
In male and female mice at 1000 ppm as compared with controls (p<0.0001).
0070h -7- 11/17/86
-------
The kidneys of male mice exposed to 1000 ppm had significantly Increased
Incidences of hyperplasla and karyomegaly of renal tubule epithelial cells
compared with controls (p<0.0001). The kidney lesions were first observed
at 12 months and became more severe as exposure continued. Hale mice
exposed to 1000 ppm also had significantly Increased Incidences of degenera-
tion and atrophy of seminiferous tubules (p=0.001) and of the spleen
(p<0.0001). The Incidence of degeneration and atrophy of the cerebellar
granular layer was also Increased In 1000 ppm exposed male (p<0.0001) and
female (p<0.05) mice compared with controls. An Increase 1n the Incidence
of atrophy and degeneration of the seminiferous tubules of male rats exposed
to 1000 ppm chloromethane was the only treatment-related hlstopathologlcal
lesion observed In rats.
A series of reports describe studies In which several species were
exposed to chloromethane vapor 6 hours/day, 6 days/week for up to 64 weeks
(Smith and von Oettlngen, 1947a,b; Smith, 1947; Dunn and Smith, 1947).
Exposure levels varied from as high as 4000 ppm (8260 mg/m3) to a low of
300 ppm (620 mg/m3). Deaths In all species occurred 1n 1-37 days at
concentrations >1000 ppm (Smith and von Oettlngen, 1947a). Rats were the
only species that had no mortality In 211 days at 500 ppm (1033 mg/m3).
Toxic effects observed In dogs exposed to 500 ppm for up to 29 weeks were
ataxlc, and had severely Impaired gait and tremors. At 500 ppm, monkeys
became emaciated and prostrate before death at 16-17 weeks. Mice, rabbits
and rats also experienced neuromuscular effects that often resulted 1n
Inability to use the hind legs. No toxic effects were observed In any
species exposed to 300 ppm for 64 weeks. The hlstopathologlcal changes In
animals exposed to -1000 ppm for 6 hours/day, 6 days/week until death, were
variable degrees of necrosis of the convoluted tubules of the kidneys In
0070h -8- 11/17/86
-------
mice and rats, renal changes associated with hemogloblnurla In mice and
occasionally In dogs, and a low to moderate amount of fatty metamorphosis of
the liver and kidneys of mice, rats, rabbits and guinea pigs (Dunn and
Smith, 1947).
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding teratogenlc and reproductive
effects of chloromethane following oral administration could not be located
In the available literature.
3.3.2. Inhalation. In a study by Holkowsk1-Tyl et al. (1983a), groups of
74-77 female C57BL/6 mice that were mated to C3H male mice were exposed to
chloromethane at 0, 250, 500 or 750 ppm (0, 516, 1033 or 1544 mg/m3) for 6
hours/day on gestation days 6-18. On gestation day 18, dams were killed.
Dams exposed to 750 ppm had decreased body weights, tremors, convulsions and
ataxla, and were hypersensitive to touch or sound. During the exposure
period, six mice died and one was killed In extremis In the 750 ppm exposure
group. The fetuses of both the 750 and 500 ppm groups had significantly
(p<0.05) Increased Incidences of heart defects compared with controls. No
effects were observed 1n the 250 ppm exposed group.
In a similar study by Wolkowsk1-Tyl et al. (1983b), groups of 25-33
pregnant Fischer 344 rats and C57BL/6 mice were exposed to chloromethane
vapor at 0, 100, 500 or 1500 ppm (0, 207, 1033 or 3098 mg/m3) for 6
hours/day on gestation days 7-19 (rats) and gestation days 6-17 (mice).
Rats and mice were sacrificed Just before parturition and the numbers of
live and resorbed fetuses were determined. Fetuses were then examined for
abnormalities. In rats, maternal food consumption, body weight gain and
terminal body weight were reduced at the high concentration. Fetal toxlc-
Hy, manifested as statistically significantly reduced fetal body weights
0070h -9- 11/17/86
-------
(both sexes) and reduced fetal crown-rump length (females only), was also
noted at the high concentration. No chloromethane-lnduced abnormalities
were observed In rat fetuses. In mice, 1500 ppm chloromethane was severely
toxic to dams after >4 days of exposure. Mice 1n the high-exposure group
were killed In extremis on gestation days 10-14. Necropsy of the dams
showed necrosis of neurons In the Internal granular layer of the cerebellum.
No maternal toxldty or fetotoxldty was observed In mice at the other expo-
sure levels. Fetuses from the 500 ppm exposed dams showed a statistically
significant (p<0.05) Increase 1n the number of heart defects. At 100 ppm,
no embryofetal toxlclty or teratogenlclty was observed 1n mice.
Chloromethane has been shown to cause reproductive effects 1n male rats.
In a study by Morgan et al. (1982), groups of 10 male Fischer 344 rats were
exposed to 0, 2000, 3500 or 5000 ppm (0, 4130, 7228 or 10,325 mg/m3)
methyl chloride vapor, 6 hours/day for 5 days, to filtered air for 2 days,
and then to chloromethane for 4 more days. After the last exposure, the
rats were killed. Hlstologlcal examination showed that all rats at the 2000
and 3500 ppm exposure levels had minimal testlcular degeneration, while at
5000 ppm all rats had severe testlcular degeneration. No testlcular lesions
were observed In control rats.
In a study by Chapln et al. (1984), adult male Fischer 344 rats were
exposed to 3500 ppm (7228 mg/m3) chloromethane, 6 hours/day for 5 days, to
filtered air for 3 days, and then to chloromethane, 6 hours/day for another
4 days. Control rats were exposed to filtered air. On postexposure days 5,
7, 9, 11, 13, 15, 19 and 70, groups of six or eight treated and two control
rats were killed. On day 9, h1stopatholog1cal examination of the testls
showed a delay In spermlatlon. On days 13-19, all treated rats showed
varying degrees of disruption and disorganization of the seminiferous
epithelium, which became more advanced as time from treatment Increased.
0070h -10- 11/17/86
-------
Granulomas of the epldldymls were observed on day 19. Most (70-90%) of the
seminiferous tubules of rats sacrificed on day 70 postexposure were
shrunken, and the remaining tubules showed varying degrees of spermatogene-
sls recovery. Chapln et al. (1984) also examined testosterone levels and
found that serum testosterone concentrations showed a time-dependent
decrease during the five consecutive chloromethane exposures (6 hours/day
for 5 days).
In a dominant lethal assay, Working et al. (1985a) exposed groups of 40
male Fischer 344 rats to chloromethane vapor at 0, 1000 or 3000 ppm (0, 2065
or 6195 mg/m3), 6 hours/day for 5 days. Each treated male was bred to one
female weekly for 8 weeks. Female rats were killed 12-17 days after mating
and data for dominant lethal effects were gathered. The results showed that
reproductive performance and fertility of male rats exposed to 1000 ppm did
not vary significantly from controls. At week 2, mating performance was
depressed and at weeks 2 and 3 postexposure there were significantly fewer
fertile males In the 3000 ppm treatment group. Though not significant, the
percentage of fertile males 1n the 3000 ppm group remained less than
controls throughout the breeding period. A significant Increase 1n
prelmplantatlon loss at week 3 postexposure was the only dominant lethal
parameter that differed from control values. The number of live and total
Implants from the 3000 ppm exposure group was decreased throughout the
8-week breeding period. Most of the decrease was a result of Increased
prelmplantatlon loss. This loss was significant at weeks 2, 3, 4, 6 and 8
postexposure. Significantly Increased postlmplantatlon loss occurred only
at 1 week postexposure. From these results, the authors concluded that the
postlmplantatlon losses may have been related to chloromethane-lnduced
0070h -11- 11/17/86
-------
dominant lethal mutations In sperm 1n the vas deferens and epldldymls at the
time of exposure, while the pre1mplantat1on losses may have been- a result of
cytotoxlc effects as well as genotoxlc effects.
In a second study by Working et al. (1985b), groups of 80 male rats were
exposed to chloromethane vapor at 0, 1000 or 3000 ppm (0, 2065 or 2195
mg/m3}, 6 hours/day for 5 days. Five rats from each group were killed
every week for 8 weeks and at 16 weeks postexposure. Rats exposed to 3000
ppm had sperm granulomas 1n the caudal epldldymls (15/39), which were first
observed 16 days after the start of chloromethane exposure. Testes of the
1000 ppm exposed group exhibited normal morphology. In the 3000 ppm exposed
group, testes showed evidence of disruption of spermatogenesls. Signs of
toxldty were still evident 8 weeks postexposure, but at 16 weeks post-
exposure most of the seminiferous tubules (50-90%) appeared normal. Sperm
counts from the 3000 ppm exposure group were significantly decreased by 1
week postexposure, and there was an Increased number of sperm with abnormal
head morphology. By the third week following exposure, sperm motHlty was
depressed and there was an Increase In the frequency of headless sperm. By
week 16 (except for sperm count which remained low), other parameters were
near normal. No effects on sperm were noted 1n the rats exposed to 1000 ppm.
Hamm et al. (1985) conducted a 2-generat1on reproductive study In
Fischer rats exposed to chloromethane vapor. Groups of 40 male and 80
female rats were exposed to chloromethane vapor at 0, 150, 475 or 1500 ppm
(0, 310, 981, 3098 mg/m3), 6 hours/day, 5 days/week for 10 weeks. After
10 weeks, each male was mated to two exposed females and the exposure was
changed to 6 hours/day, 7 days/week. After a 2-week mating period, males
were removed from exposure and matt! for an additional 2 weeks with
0070h -12- 11/17/86
-------
unexposed females. Females 1n treated groups were not exposed from gesta-
tion day 18 to postnatal day 4. For 10 weeks, members of the F. genera-
tion were exposed to the same chloromethane concentration as their parents
(0, 150 and 475 ppm) and were then mated.
Results showed a significant decrease In body weight gains In the 1500
ppm Fn males and females after 2 weeks, and 1n the 475 ppm males and
females after 57 days. No Utters were produced from males exposed to 1500
ppm with either exposed or unexposed females. Exposed and unexposed females
mated to 475 ppm males produced significantly fewer Utters than controls.
No effects on Utter size, sex ratio, pup viability, pup survival or pup
growth were noted 1n the 475 and 100 ppm groups. Results of the F. breed-
Ings were not significantly different from controls, either biologically or
statistically, although a trend toward decreased fertility was noted at
475 ppm.
3.4. TOXICANT INTERACTIONS
Putz-Anderson et al. (1981a) studied the effects of chloromethane and
dlazepam on CNS performance In humans. Volunteers were exposed to chloro-
methane at 200 ppm (413 mg/m3) for 3 hours, were given 10 mg dlazepam, or
received both treatments. Performance was then measured In a visual-
vigilance task, a dual task and a time discrimination task. Dlazepam caused
a 10% average decrease In overall performance; chloromethane caused a
decrease of 4X. Combined, the two treatments caused an average decline of
13.5% Indicating that the effects of methyl chloride and dlazepam are
additive.
Putz-Anderson et al. (1981b) also studied the effects of chloromethane
with caffeine and ethanol on humans. Male and female volunteers were
exposed to methyl chloride at 0 or 200 ppm (413 mg/m3) for 3 hours along
0070h -13- ; 08/06/86
-------
with a drug treatment of ethanol (0.8 ml/kg absolute ethanol), caffeine (3
mg/kg) or a placebo. Performance tests used were the same as In the
previous study. The results showed that chloromethane exposure at 200 ppm
did not significantly change the effects of ethanol or caffeine.
0070h -14- 08/06/86
-------
4. CARCIMOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the potential carclnogenlclty of chloromethane
In humans by oral or Inhalation exposure could not be located 1n the
available literature.
4.2. BIOASSAYS
4.2.1. Oral. Pertinent data regarding the potential carclnogenlclty of
chloromethane 1n animals following oral exposure could not be located 1n the
available literature.
4.2.2. Inhalation. A 2-year Inhalation study In mice and rats was con-
ducted (CUT, 1981), 1n which groups of 120 male and 120 female B6C3F1 mice
and equal numbers of male and female Fischer rats were exposed to chloro-
methane vapor at 0, 50, 225 or 1000 ppm (0, 103, 465 or 2065 mg/m3) for 6
hours/day, 5 days/week. At 6, 12, 18 and 24 months, 5-20 rats and mice/sex/
group were killed. High mortality was observed In mice 1n the 1000 ppm
group so that only two survived until 21 months, at which time they were
sacrificed. Comprehensive hlstologlcal examinations of all control and 1000
ppm mice and rats were made. Hlstologlcal examination of the 50 and 225 ppm
groups were limited to testes, epidldymis, kidneys, liver and lungs for rats
and liver, kidneys, spleen and brain for mice.
Although survival appeared to be reduced In 1000 ppm mice of both sexes,
a statistically significant Increase In mortality occurred only 1n females.
A significant Increase 1n the Incidence of renal tumors was observed In male
mice. Table 4-1 shows the numbers of male mice killed or dying, and the
Incidence of renal tumors In each month from the 12th month (when the first
kidney tumor was found). Tumor types found were renal cortical adenomas,
renal cortical adenocardnomas, papillary cystadenomas, tubular cystadenomas
0070h -15- 08/06/86
-------
TABLE 4-1
Numbers of Male Mice Sacrificed or Dying and Kidney Tumor
Prevalence 1n Months 13-24a»b
Month
13
14
15
16
17
18
19
20
21
22
23
24
TOTAL
Control
12
1
3
0
2
1
6
3
6
3
4
26
67
50 ppm
10
0
0
0
0
0
5
4
5
0
1
36
61
225 ppm
10
0
0
0
0
0
5
2
1
3
0
36 (2A)
57
1000 ppm
11 (1A)
3
4
2
3 (1A, 1C)
3
11 (3A)
17 (4A)
24 (4A, 4C)
3
0
1
82
aSource: CUT, 1981; NIOSH, 1984
^Parentheses Indicate numbers of mice with kidney tumors, classified as
adenomas (A) or carcinomas (C)
0070h
-16-
08/06/86
-------
and papillary cystadenocarclnomas. The Incidences of kidney tumors, as
Indicated on Table 4-1, were 0/67 controls, 0/61 1n the 50 ppm group, 2/57
In the 225 ppm group and 18/82 1n the 1000 ppm group. The above Incidences
do not account for kidney tumors that may have developed If the mice that
were sacrificed at Interim kills or died during the experiment had lived to
24 months. To correct for Intercurrent mortality, the method described by
Peto et al. (1980) was applied. The "corrected" Incidences of renal tumors
1n male mice are presented In Table 4-2. No evidence of treatment-related
oncogenldty was observed In female mice or male or female rats.
4.3. OTHER RELEVANT DATA
Chloromethane has been shown to be positive for reverse mutation 1n
Salmonella typhlmurlum strains TA1535 (Andrews et al., 1976) and TA100
(Simmon et al., 1977; Simmon, 1978, 1981) both 1n the presence and absence
of S-9 metabolic activation. Chloromethane has also been found to be posi-
tive for forward mutations In £. typhlmurlum TA677 and human lymphoblasts
and for SCE 1n human lymphoblasts without metabolic activation (Fostel et
al., 1985). In a dominant lethal study, Working et al. (1985a,b) found that
Chloromethane Induced dominant lethal mutations In mature sperm of Fischer
344 rats exposed to 3000 ppm (6195 mg/m3), 6 hours/day for 5 days.
4.4. HEIGHT OF EVIDENCE
The Increased Incidence of kidney tumors In male mice, as supported by
the positive mutagenlclty data, constitutes limited animal evidence for
carc1nogen1c1ty and as such means that Chloromethane would fall within a
U.S. EPA Group C classification, "possible" human carcinogen (U.S. EPA,
19865).
0070h . . -17- 07/30/87
-------
OJ
u
^
~?
J?
/"^
03
OJ*S
'"** j*
^2 r\
^L GJ
C ^x
« i/i
m*
CD *"" **
l_
3 in
Q.
X >»
on ^3
cn o
* C
P ^
0 r-
' ^
C_> C
o >>
u -o
c cu
CD t/i
* 0
O Q.
Q. X
U
c
CD
O
"
U
ns
*»
0>
u
L. C
O O)
E "0
h** W
c
0)
a.
^^
t
L.
g
3
H-
^j
^ C
u O>
1 O
C >> -
O ^3 i/^
**" 3 ^Z
«-> *J jJ
->
C
C O)
_o e
t-t fO
3 H-
_ -^
m
E
x
1/1 £
O *-»
a
E
a.
r- r r~
^ v^ m
x -x v.
O O CM
m
C £
a, o
o c
o
r^ l^
(^ T3
O ^
O)
c
o
Z Z ^
CM CM CM
I/I I/I I/I
555
c c c
o o o
E E E
CM CM CM
o o o
'*''**'**
a. a. a.
333
<^«« ^**
co m
^ » CO ^D
O i «f
o o >n
in CM
re >>
E ^
O "3
c i 2
cu i- E
o o
T3 Q. C
^^ IQ <^
wi a. u
>> L.
O ^3 *O
C U
>. 03 O
L. C
(^ LB CL)
^^ ^3 ^3
r- r fO
- 3 <-
Om ^ I/I
fD 3 >>
CL * o
u
p^
00
^^
CM
CM
l/l
2 >>
E i-
O T3
C i ITJ
CU P- £
§0 o
TJ a. e
m ^rf <^ *»
CU 0 > W
. T3 O
(!_(- C
*J ft] rfy 1 fy
OO^*O T3
*- O ( r f^
t-> C <- 3 *-
^ cu QL J3 vi
O T3 <« 3 >«
O 03 d *-* O
>^
c
o
^
CM
-
"fl3 2
CU »
o c
VI
O i
E «M
tff^
in
vO
o
CM
*n*r
0
o
o
r-
o
00
f~"
*_*
4
^~
"
cu
0
CU
a.
a.
P
P
4->
E
CD
^^
^3
£
ns
^
E
^_,
c
cu
i_
3
j*
*p
^
C
P
u-
o
CU
^^
3
o
i rg
CO
cn i/i
i CU
u
c
<-* -a
U 0
c
*^~
CU
U L.
t- P
3 E
P 3
00 H-
,
^1
CO
u
CD
r
.a
rQ
U
a.
a.
eQ
*-*
P
3£
II
<
Z
0070h
-18-
08/06/86
-------
5. REGULATORY STANDARDS AND CRITERIA
The ambient water quality criterion for chloromethane 1s 19 mg/i (U.S.
EPA, 1982). This level Is based on an RfD of 0.54 mg/kg/day, which was
calculated from a TLV of 50 ppm (105 mg/m3) (U.S. EPA, 1980a). The AC6IH
(1985, 1986) TLV of 50 ppm Is based on human exposure data that show no
Irreversible systemic effects at 100-200 ppm, and the observations of Repko
et al. (1976) that neurotoxlc effects may occur at lower exposures. The
STEL adopted by ACGIH (1985) 1s 100 ppm (205 mg/m3) for 15 minutes. A
permissible exposure limit for chloromethane Is not listed by OSHA (1985).
0070h -19- 11/17/86
-------
6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDc)
*>
Since chloromethane has been shown to be a carcinogen 1n male mice, an
RfDc will not be determined.
w
6.2. REFERENCE DOSE (RfD)
Since chloromethane has been shown to be a carcinogen In male mice, an
RfD will not be determined.
6.3. CARCINOGENIC POTENCY (q-,*)
6.3.1. Oral. Pertinent data regarding the carcinogenic potential of
chloromethane following oral administration could not be located 1n the
available literature. Because of the lack of oral data, the U.S. EPA
(1986a) calculated an oral q * from the Inhalation data (see Section
6.3.2.) by applying an absorption factor of 0.5. The resultant value of
1.26xlO~2 (mg/kg/day)"1 was obtained.
6.3.2. Inhalation. An Inhalation q * was calculated using the multi-
stage model of Howe and Crump (1982) from the CUT (1981) study that showed
an Increase 1n kidney tumors from male mice. A statistically significant
Increase 1n the Incidence of benign and malignant kidney tumors was observed
1n the high-dose male mice compared with controls (see Section 4.2.2.).
Because the CUT (1981) study used Interim kills, the Incidences of kidney
tumors were corrected for Intercurrent mortality by the method of Peto et
al. (1980). The q * was calculated using the multistage model developed
by Howe and Crump (1982). The data used to calculate the Inhalation q,*
are presented 1n Table 6-1. The unadjusted q * 1s 4.77xlO~*
(mgVkg/day)"1 while the human q,* Is 6.32xlO~3 (mg/kg/day)"1.
0070h -20- 06/16/87
-------
TABLE 6-1
Derivation of a q-j* for Inhalation Exposure
Compound: Chloromethane
Reference: NIOSH, 1984; CUT, 1981
Specles/straln/sex: mouse, B6C3F1, male
Route/vehicle: Inhalation, air
le = 24 months
LE = 24 months
L = 24 months
bw = 0.03 kg (measured)
Tumor type and site: kidney adenoma or carcinoma
Experimental Doses
or Exposues
(mg/m3, 6 hours/day,
5 days/week)
Transformed Dose
(mg/kg/day)
Incidence
No. Responding/No. Examined
0
103
656
2065
0
24
152
480
0/67
0/61
2/57
22/82
Unadjusted q-|* from study = 4.7678305x10'* (mg/kg/day)'1
Human q-]* = 6.3238234xlO~3 (mg/kg/day)'1
0070h
-21-
02/18/87
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1985.
TLVs: Threshold Limit Values for Chemical Substances 1n the Work Environ-
ment. Adopted by ACGIH with Intended changes for 1985-1986. Cincinnati,
OH. p. 23.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986.
Documentation of the Threshold Limit Values for Substances In Workroom A1r.
4th ed. with supplements through 1984. Cincinnati, OH. p. 268-269.
Andrews, A.W., E.S. Zawlstowskl and C.R. Valentine. 1976. A comparison of
the mutagenlc properties of vinyl chloride and methyl chloride. Mutat. Res.
40: 273-276.
Chapln, R.E., R.O. White, K.T. Morgan and J.S. Bus. 1984. Studies of
lesions Induced In the testls and epldldymls of F-344 rats by Inhaled methyl
chloride. Toxlcol. Appl. Pharmacol. 76(2): 328-343.
CUT (Chemical Industry Institute of Toxicology). 1981. Final report on
24-month Inhalation study on methyl chloride. Prepared by Battelle-Columbus
Laboratories, Columbus, OH. December 31.
Davis, D.D., G. Machado, B. Conaway, Y. Oh and R. Watson. 1976. A
temperature dependent kinetics study of the reaction of OH with CH-CL,
CH.CL2, CHCL3 and CHgBR. J. Chem. Phys. 65: 1268-1274.
0070H -22- 02/18/87
-------
Davis, D.D., W.L. Chamelders and C.S. K1ang. 1982. Measuring atmospheric
gases and aerosols. Nature. 295: 186.
Dining, W.L. 1982. Atmospheric environment. In: Environmental Risk
Analysis for Chemicals, R.A. Conway, Ed. Van Nostrand Relnhold Co., New
York, NY. p. 154-197.
Dunn, R.C. and W.W. Smith. 1947. Acute and chronic toxlclty of methyl
chloride. IV. Hlstopathologlc observations. Arch. Pathol. 43: 296-300.
Evtushenko, G.Y. 1966. No title provided. Gig. Tr. Prof. Zabol. 10: 20.
(Russian with English translation) (Cited 1n U.S. EPA, 1980a)
Fostel, J., P.P. Allen, E. Bermudez, A.D. Kllgermon, J.L. WHmer and T.R.
Skopek. 1985. Assessment of the genotoxlc effects of methylchloMde 1n
human lymphoblasts. Mutat. Res. 155(1-2): 75-82.
Hamm, I.E., Jr., T.H. Raynor, M.C. Phelps, et al. 1985. Reproduction In
F-344 rats exposed 1n methyl chloride by Inhalation for two generations.
Fund. Appl. Toxlcol. 5(3): 568-577.
Hansch, C. and A.J. Leo. 1985. MedChem Project Issue No. 26. Pomona
College, Claremont, CA.
Howe, R.B. and K.S. Crump. 1982. GLOBAL 82. A computer program to
extrapolate quantal animal tox1c**,y data to low doses. Prepared for Office
of Carcinogen Standards, OSHA, U.S. Dept. of Labor, Washington, DC. Control
No. 41USC202C3.
0070h -23- 02/18/87
-------
Khalll, M.A.K. and R.A. Rasmussen. 1983. Gaseous tracers of arctic haze.
Environ. Sd. Techno!. 17: 157-164.
Landry, T.O., T.S. Gushow, P.M. Languardt, J.M. Wall and M.J. McKenna.
1983. Pharmacok1net1cs and metabolism of Inhaled methyl chloride In the rat
and dog. Toxlcol. Appl. Pharmacol. 68(3): 473-486.
Lyman, W.J., W.F. Reehe and O.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. Environmental Behavior of Organic Compounds.
McGraw-Hill Book Co., New York. p. 4-9, 5-5, 13-15, 15-26, 15-27.
Mackay, D. and W.Y. Shu1. 1981. A critical review of Henry's Law Constants
for chemicals of environmental Interest. J. Phys. Chem. Ref. Data. 10(4):
1190.
Mitchell, R.I., K. Pavkov, R.M. Everett and D.A. Holzworth. 1979. A 90-day
Inhalation toxicology study In rats and mice exposed to methyl chloride.
Submitted by DuPont DeNemours and Co., Inc. OTS, Washington, DC. OTS No.
878211740, Microfiche No. 205861.
Morgan, A., A. Black and D.R. Belcher. 1970. The excretion In breath of
some aliphatic halogenated hydrocarbons following administration by Inhala-
tion. Ann. Occup. Hyg. 13: 219-233.
Morgan, K.T., J.A. Swenberg, T.E. Hamm, Jr., R. Wolkowsk1-Tyl and M. Phelps.
1982. Hlstopathology o. acute toxic response 1n rats and mice exposed to
methyl chloride by Inhalation. Fund. Appl. Toxlcol. 2: 293-299.
0070h -24- 02/18/87
-------
NIOSH (National Institute for Occupational Safety and Health). 1984.
Carcinogenic Risk Assessment for Occupational Exposure to Monohalomethanes.
NTIS PB85-111623.
Nolan, R.J., O.L. Rick, T.O. Landry, L.P. McCarty, G.L. Agin and J.H.
Saunders. 1985. Pharmacoklnetlcs of Inhaled methyl chloride (CH_C1) 1n
male volunteers. Fund. Appl. Toxlcol. 5(2): 361-369.
OSHA (Occupational Safety and Health Administration). 1985. Permissible
Exposure Limits Code of Federal Regulations. 29: 1910.1000.
Peto, R., M.C. P1ke, N.E. Day, et al. 1980. Guidelines for simple, sensi-
tive significance tests for carcinogenic effects In long-term animal experi-
ments. ln_i Long-term and Short-term Screening Assays for Carcinogens. A
Critical Appraisal. IARC Monographs, Supplement 2. WHO, Lyon, France.
p. 378.
Putz-Anderson, V., J.V. Setzer, J.S. Croxton and F.C. Phlpps. 1981a.
Methyl chloride and dlazepam effects on performance. Scand. J. Work
Environ. Health. 7: 8-13.
Putz-Anderson, J.V. Setzer and J.S. Croxton. 1981b. Effects of alcohol,
caffeine and methyl chloride on man. Psycho!. Rep. 48(3): 715-725.
Repko, J.D. and S.M. Losley. 1979. Behavioral, neurological and toxic
effects of methyl chloride. A review of the literature. CRC CrH. Rev.
Toxlcol. 6(4): 283-302.
0070h -25- 02/18/87
-------
Repko, J.D., P.O. Jones, L.S. Garcia, Jr., E.J. Schneider, E. Roseman and
C.R. Corum. 1976. Behavioral and neurological effects of methyl chloride.
Behavioral and neurological evaluation of workers exposed to Industrial
solvents: Methyl Chloride. U.S. DHEW (NIOSH) Publ. 77-125. p. 199.
Simmon, V.F. 1978. Structural correlations of carcinogenic and mutagenlc
alkyl halldes. Struct. Correl. Cardnog. Mutagen. U.S OHEH Publ. (FDA);
ISS FDA 78-1046.. p. 163-171.
Simmon, V.F. 1981. Applications of the Salmonella/mlcrosome assay. Short-
term tests. Chem. Carclnog. p. 120-126.
Simmon, V.F., K. Kauhanen and R.G. Tordlff. 1977.. Mutagenlc activity of
chemicals Identified 1n drinking water. Dev. Toxlcol. Environ. Sc1. 2:
249-258.
Singh, H.B., L.J. Salas and R.E. Stiles. 1982. Distribution of selected
gaseous organic mutagens and suspect carcinogens 1n ambient air. Environ.
Sc1. Technol. 16: 872-880.
Smith, W.W. 1947. The acute and chronic toxlclty of methyl chloride.
III. Hematology and biochemical studies. J. Ind. Hyg. Toxlcol. 29: 185-189.
Smith, W.W. and W.F. von Oettlngen. 1947a. The acute and chronic toxlclty
of methyl chloride. I. Mortality resulting from exposure to methyl chloride
In concentrations of 4000-^30 parts per million. J. Ind. Hyg. Toxlcol. 29:
47-52.
0070h -26- 02/18/87
-------
Smith, W.W. and W.F. von Oettlngen. 1947b. The acute and chronic toxlclty
of methyl chloride. II. Symptomology of animals poisoned by methyl chloride.
J. Ind. Hyg. Toxlcol. 29: 123-128.
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for Halomethanes.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regu-
lations and Standards, Washington, DC. EPA 440/5-80-051. NTIS PB81-117624.
U.S. EPA. 1980b. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1982. Errata for Ambient Water Quality Criteria Document for
Halomethanes. Prepared by the Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH for the
Office of Water Regulations and Standards, Washington, DC.
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response, Wash-
ington, DC.
U.S. EPA. 1986a. Health and Environmental Effects Profile for Methyl
Chloride. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Solid Waste and Emergency Response, Washington, DC.
0070h -27- 06/17/87
-------
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
Wolkowsk1-Tyl, R., A.D. Lawton, H. Phelps and I.E. Hamm, Jr. 1983a. Evalu-
ation of heart malformations 1n B6C3F1 mouse fetuses Induced by in utero
exposure to methyl chloride. Teratology. 27(2): 197-206.
Wolkowsk1-Tyl, R., M. Phelps and T.K. Oavls. 1983b. Structural terato-
genlclty evaluation of methyl chloride 1n rats and mice after Inhalation
exposure. Teratology. 27(2): 181-196.
Working, P.K., J.S. Bus and T.E. Hamm, Jr. 1985a. Reproductive effects of
Inhaled methyl chloride In the male F-344 rat. I. Mating performance and
dominant lethal assay. Toxlcol. Appl. Pharmacol. 77(1): 133-143.
Working, P.K., J.S. Bus and T.E. Hamm. 1985b. Reproductive effects of
Inhaled methyl chloride In the male F-344 rat. II. Spermatogonlal toxldty
and sperm quality. Toxlcol. Appl. Pharmacol. 77: 144-157.
0070h -28- 06/17/87
-------
a;
u
L.
01
0)
oe
i-
< o
Q.
Q.
O)
c
0)
I
o
ti-
ll)
JS
fO
O
4J
0)
O
o
V.
0>
L.
a
i/» >»
O ns
Ol
o.
O
0£
f CO
oo en
i to
-i O
u z
X .*
CM >^
CO O>
» E c
oi o «-
ecu
o o> u
n *
E a; i
EEC;
ex 3 -
Q.UI v. «*
^o i/> CM
o o >»
O CM «3
O TS O
r L.
o ui
L_ I/I >1
O vO - J= T3
un >>--> -o
un va ?o c x.
CM -o o o»
CM -^ E J^
CO i/l *x
-o i- ^- o»
o i a
co
0)
0070h
-29-
02/18/87
------- |