METHYLENE CHLORIDE
Explanation
This compound was previously evaluated for an ADI for man by the
Joint FAO/WHO Expert Committee on Food Additives in 1980 (see Annex I,
Ref. 51). A toxicological monograph was published in 1980 (see Annex
I, Ref. 52). Since then the following data have been published, and
are summarized in the following monograph.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Metabolism
Dichloromethane and other dihalomethanes are metabolized to
carbon monoxide catalysed by the hepatic mixed function oxidase
system. This pathway has been proposed to proceed through an oxygen
insertion reaction yielding a formyl halide intermediate which
decomposes to yield carbon monoxide. Another pathway, possibly
involving a glutathione transferase located in the liver cytosol
fraction, yields formaldehyde or formic acid (Ahmed et al., 1980;
Ahmed & Anders, 1976),
Label from 14C-dichloromethane is covalently bound in vitro
when added to rat liver microsomal systems. Binding was increased if
the animal had been pre-treated with phenobarbital (Ahmed et al.,
1980).
Male Sprague-Dawley rats (body weight approximately 250 g) given
a single 1 mg dose of 14C-methylene chloride by gavage metabolized a
greater percentage of the dose than animals given 50 mg. Over 48
hours, only about 12% of the 1 mg dose was exhaled as unchanged
methylene chloride as compared to 72% of the 50 mg dose.
Proportionately greater amounts of the 1 mg dose were found as expired
CO2 or CO or were present as metabolites in urine or faeces. At the
1 mg dose the major metabolites were CO2 (35% of the administered
dose) and CO (31%). After 48 hours relatively little activity from
either dose, less than 10% total, was present in organs, skin or
carcass. The authors indicated a dose-dependent metabolism for
methylene chloride with saturation of the metabolic pathways at the
50 mg dose (McKenna & Zempel, 1981).
A total of 11 male and three female human volunteers were exposed
to 50, 100, 150, or 200 ppm (0.005, 0.01, 0.015 or 0.02%) of methylene
chloride in air for 7.5 hours per day for five consecutive days. About
70% of the unchanged methylene chloride was absorbed and about 25-34%
of the absorbed compound was ultimately excreted in expired air as CO,
less than 5% was expired as methylene chloride after exposure had
ceased (DiVincenzo & Kaplan, 1981).
Suspensions of hepatocytes prepared from the livers of male
Sprague-Dawley rats were incubated with 42 micromoles of 14C-labelled
dichloromethane over a 30 minute incubation period, alkylation of
lipid and protein by labelled metabolites of dichloromethane was
observed, however, no alkylation of DNA or RNA could be detected
(Cunningham et al., 1981). A theoretical pharmacokinetic computer
model was constructed to compare simulated methylene levels and
metabolite production in mice administered methylene chloride at
1000 mg/kg, five days per week in corn oil by gavage or at 250 mg/kg
in the drinking-water. For maximum peak height and total area under
the liver concentration curve (AUC), higher levels were obtained by
gavage administration. Corn oil gavage also gave higher values for the
AUC above the apparent Michaelis constants (KM) for CO2 and CO
production, but the drinking-water route gave a longer time interval
so that AUC values were greater than the apparent KM. According to the
model, more metabolites may have been produced on a daily basis in
drinking-water than by the gavage route (National Coffee Association,
1982).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
The doses selected for the following NTP gavage studies were
based on the conventional guidelines used by the NTP for estimating an
MTD, namely no more than 10% weight decrement as compared to the
appropriate control group and do not produce mortality, clinical signs
of toxicity or life-shortening pathological lesions other than those
which may be related to a neoplastic lesion. Details of the studies
are provided in the section on short-term studies (NTP, 1982).
Groups of 50 male and 50 female Fischer-344/N rats were
administered 0, 500 or 1000 mg/kg bw of "Food Grade"* dichloromethane
by gavage in a corn oil vehicle five days per week for 103 weeks
(volume of corn oil was 5 ml/kg bw). Two batches of dichloromethane
were used during the course of the study. The animals were housed five
per cage. In addition there was an untreated control group consisting
of 50 male and 50 females. After the 103 week dosing period, animals
were maintained until terminal sacrifice at 106 or 107 weeks. Complete
gross and histopathological examinations were performed on animals
found dead and on those sacrificed at the end of the study. Mean body
weights of dosed rats were slightly lower than those of vehicle
* A detailed analysis is given in Appendix E of NTP, 1982.
controls throughout most of the study. The effect was most pronounced
in the high-dose females. The survival of the high-dose males was
significantly less than that of the vehicle controls. In females, the
survival of the high dose was significantly less than that of the
vehicle controls and the low dose. In males, survival to the end of
the study was 40/50 in the vehicle control, 33/50 in the low dose and
24/50 in the high dose. The corresponding values in the females were
35/50, 25/50 and 12/50. A large number of animals died from gavage
errors. A total of three vehicle control, nine low-dose and 10
high-dose males died from this cause. In females the corresponding
values were 1, 17 and 18. The report suggested that the deaths from
gavage errors may not have all been due to gavage error per se, but
that a local or systemic action of the solvent may increase the
animals susceptibility to gavage accident. In the liver, neoplastic
nodules occurred in male and female rats with a significant positive
trend and significantly increased incidence as compared to the vehicle
treated animals. The incidence in males was 5/49 untreated controls,
2/48 vehicle control, 8/50 low dose and 9/47 high dose. In females the
corresponding incidences were: 6/50, 3/50, 13/50 and 10/49,
Hepatocellular carcinomas were found in one vehicle control and one
low-dose male and one high-dose female. No significant treatment-
related non-neoplastic lesions were noted in the livers of treated
rats. There was a significant increase in the incidence of adrenal
cortical adenomas in both males and females. The incidence was 1/49,
3/50 and 7/47 in vehicle control, low- and high-dose males. The
corresponding incidence in females was 3/50, 8/50 and 5/49. The
incidence of pancreatic acinar cell adenomas in dosed male rats
occurred with a significant positive trend. The incidence in males was
1/48 in untreated controls, 10/48 in vehicle controls, 17/50 at the
low dose and 9/47 at the high dose. The incidence in the vehicle
controls was significantly higher than in the untreated controls.
There was a significant positive trend and a significant increase in
the incidence of C-cell carcinoma in high-dose male rats as compared
to the vehicle control. However, the incidence of C-adenoma alone or
the combined incidence of C-cell adenomas and carcinomas was not
significantly increased as compared to male vehicle controls. These
rumours were not significantly increased in dosed female rats,
although the incidence of C-cell hyperplasia was significantly
increased over the vehicle controls; but not the untreated control,
which had a higher incidence (13/50) than the high dose (12/50)
(National Toxicology Program, 1982).
Groups of 50 male and 50 female B6C3F1 mice were administered 0,
500 or 1000 mg/kg bw of "Food Grade" dichloromethane by gavage in corn
oil vehicle five days per week for 103 weeks. Two batches of
dichloromethane were used during the course of the study. (The volume
of corn oil was 10 ml/kg bw.) In addition, there was an untreated
control group consisting of 50 males and 50 females. Animals were
housed five per cage. After the 103 weeks dosing period, animals were
maintained for several weeks prior to terminal sacrifice at 106 or 107
weeks. Complete gross and histopathological examinations were
performed on all animals found dead and those sacrificed at the end of
the study. Mean body weights of high-dose male mice were lower than
those of vehicle control females had comparable body weights
throughout the study. In male mice, survival was not affected by
treatment; in females, survival in the high dose was significantly
decreased compared to vehicle controls or the low dose. Although the
incidence of hepatocellular adenoma was not influenced by dosing,
there was a significant positive trend in hepatocellular carcinomas in
both males and females and the incidence of this lesion was
significantly increased compared to vehicle controls in high dose
males and at both doses in females. The incidence in males was 13/48
in untreated controls, 8/48 in vehicle controls, 13/48 in low-dose and
18/49 in high-dose males. In females the corresponding incidence was
2/48, 0/49, 6/48 and 9/49. Hepatocellular carcinomas metastasized to
the lung in two low-dose and five high-dose male mice. Fatty
metamorphosis was found in the livers of nine high-dose female mice
but not in any vehicle control or low-dose females. Alveolar/
bronchiolar carcinomas occurred with a significant positive trend in
female but not male mice, but the incidence of males and females with
alveolar/bronchiolar carcinomas was not influenced by treatment
(National Toxicology Program, 1982).
The doses selected for the following drinking-water study (in
which the maximum exposure was a quarter of that used in the gavage
study) were based on pharmacokinetic and histopathology data.
Comparison of the pharmacokinetic curves of methylene chloride
administered by inhalation, and by gavage either in corn oil or water
showed that a significant change in slope occurs around 250 ppm
(0.02%) and 100 mg/kg/day, respectively. At this level there was a
significant change in the rate of formation of metabolites, as
measured by CO and CO2 in expired air. In addition the dose was
given seven days a week, rather than give in the gavage study, and
provides for a continuous rather than a discontinuous challenge.
"Food Grade" dichloromethane was administered in the drinking-
water for 24 months to groups of 85 male and 85 female Fischer-344
rats at levels of 5, 50, 125, and 250 mg/kg bw per day. There was an
additional control group (2) of 50 animals of each sex as well as an
additional high-dose/recovery group that received deionized water only
after week 78 of the study. Interim sacrifices were carried out at
weeks 26 (five animals per sex per group), 52 (10 per sex per group)
and 78 (20 per sex per group) in all groups except for the second
control group (2) and the high-dose/recovery group (2). There was no
treatment-related effect on survival, food consumption or on body
weight gain except for a slight (less than 10%) depression in weight
gain in the high-dose group. Significantly lower water consumption was
noted in all of the dosed males and in the two highest doses in the
females. Clinical chemistry and haematology studies were carried out
at weeks 52 and 78 on 10 animals per sex per dose. Slightly increased
haematocrit and haemoglobin levels were noted in the two highest doses
in males at weeks 52 and 78. At one or both time intervals, there were
apparent compound related decreases in serum alkaline phosphatase in
males and creatine, BUN, serum protein and serum cholesterol in both
sexes. There were no reported compound related changes in absolute or
relative organ weight or in gross pathological lesions. The report
stated that treatment-related histomorphological alterations of the
liver were observed and consisted of an increased incidence of
foci/areas of cell alteration in the groups given 50, 125 and
250 mg/kg of methylene chloride in both sexes. In the females, no
neoplastic nodules were observed in either of the control groups; in
the dosed groups a total of 1, 2, 1 and 4 neoplastic nodules were
observed in the animals given 5, 50, 125, 250 mg/kg respectively, of
dichloromethane for 104 weeks. While two nodules were found in the
group given 250 mg/kg for 78 weeks and then deionized water until
terminal sacrifice. There was also a treatment related increase in
fatty liver in the groups given 125 and 250 mg/kg of the test
compound. Although there was no decrease in the incidence of
foci/alteration of the liver in the high-dose/recovery group, the
incidence of fatty liver did decrease in this group suggesting a
possible regression of this effect. The report also stated that a
no-effect level of 5 mg/kg bw per day was observed (National Coffee
Association, 1982).
Groups of 129 male and 129 female Sprague-Dawley rats were
exposed to 0, 500, 1500 or 3500 ppm (0, 0.05, 0.15 or 0.35%) of
technical grade methylene chloride in the air for six hours per day,
five days per week for two years. Animals were housed not more than
three per cage. About 95 animals per sex per dose were part of the
chronic toxicity/carcinogenicity part of the study, the remainder of
the animals were utilized at interim sacrifices after six, 12, 15 or
18 months of exposure or were sacrificed for cytogenetic analysis.
There were no compound related changes in body weight gain. A
significant increase in mortality occurred in female high-dose rats
during the 18-24 month exposure period. A slight CNS depression was
noted in dosed animals during the first week of the study. There was a
significant increase in relative and absolute liver weight in males
and in absolute liver weight in females at the 18 month interim
sacrifice. No treatment-related haematological changes were noted
except that the red cell MCD and MCH indices in both males and females
tended to be increased as compared to controls. The report stated this
increase could have been a physiological adaptation to increased
carboxyhaemoglobin levels. No compound-related effects on clinical
chemistry were reported. Carboxyhaemoglobin levels were elevated as
compared to controls in males and females at all dose levels. There
were no treatment-related effects on the incidence of cytogenetic
aberrations. There appeared to be a compound-related effect on gross
pathological hepatic lesions, especially in high-dose females. There
was an increased incidence of multiple light or dark foci in the liver
and mottled livers or livers with an accentuated lobular pattern in
high dose females.
On histopathologic examination, dosed male and female rats had an
increased incidence of hepatic vacuolization, multinucleated
hepatocytes and hepatic foci/areas of cellular alterations. There was
no reported increase in malignant liver tumours, however, two of 10
females sacrificed at 18 months had hyperplastic liver nodules. There
was an increased incidence of malignant mesenchymal tumours (sarcomas)
in or around the salivary glands in high- and mid-dose males. One of
these tumours was found in a control male, five in the mid-dose males
and 11 in the high-dose males. The increased incidence was
statistically significant in the high-dose animals. In the report it
stated that the effects may have been related to viral salivary gland
infection, however, these tumours were not detected in females with
the viral infection. As compared to controls, there was an increased
number of benign mammary tumours in male and female rats; the effect
was more prominent in females. There was no apparent increase in
malignant mammary tumours in either sex (Burek et al., 1980).
Groups of 107 to 109 male and 107 to 109 female Syrian Golden
hamsters were exposed to 0, 500, 1500 or 3500 ppm (0. 0.05, 0.15 or
0.35%) of methylene chloride in air for 24 months. Interim sacrifices
were carried out at six, 12 and 19 months. There were no significant
compound-related effects on body weight gain or absolute or relative
organ weight. During the latter part of the study, mortality was
decreased in mid and high dose hamsters. Haematology parameters were
unchanged except for a compound-related increase in haemoglobin and
haematocrit in both sexes. No treatment-related effects on clinical
chemistry or urinalysis were reported. Carboxyhaemoglobin values were
in treated animals of both sexes. No compound-related increases in
gross or microscopic pathological lesions were reported in males or
females. The incidence of amyloid lesions was reported to decrease in
the treated hamsters (Burek et al., 1980).
Groups of 90 male and 90 female Sprague-Dawley rats were exposed
six hours per day, five days per week for 20 (male) or 24 (female)
months to air containing 0, 50, 200 or 500 ppm (0, 0.005, 0.02 or
0.05%) of technical grade (99.5 pure) methylene chloride. Two
additional groups of 30 females each were exposed to 500 ppm (0.05%)
of methylene chloride for 12 months and then maintained without
exposure to the test compound for 12 months (group 500/0) or were
maintained with no exposure for 12 months and then 500 ppm (0.05%) for
12 months (0/500 group). Interim sacrifice of five animals per sex per
dose groups were conducted at six, 12, 15, and 18 months. Satellite
groups of 18 females per dose level were utilized for assays of the
rate of hepatic DNA synthesis. There was no reported effect of
treatment on mortality; because of high mortality in all groups of
males they were sacrificed at 20 months. No treatment-related effects
were observed on body weight gain or absolute or relative organ
weights. In animals sacrificed at the end of the experiment, there was
a significant increase in incidence of foci of altered hepatocytes at
500 ppm (0.05%) in females and in males at 200 and 500 ppm (0.02 and
0.05%). The incidence of foci of altered cells at terminal sacrifice
was 9/25, 5/17, 10/22 and 17/27 in control, low-, mid- and high-dose
females, respectively. The corresponding incidence in males was 1/18,
3/19, 5/13 and 7/19. The incidence of this lesion is not significantly
increased, however, in either males or females if lesions observed at
the terminal sacrifice and in animals dying prior to the terminal
sacrifice are combined. There were small increases in hepatocellular
vacuolization in high-dose males and females and in multinucleated
hepatocytes in high-dose females. The incidence of rats with benign
mammary tumours was increased in dosed females (Nitschke et al.,
1982).
Special studies on mutagenicity
When 0.5 ml of dichloromethane was added to an open glass dish
within a desiccator also containing Salmonella plates (rather than
added directly to the plates) mutagenicity was observed; there was a
sixfold increase in the number of revertants in Salmonella strain
TA-100 and a twofold increase in strain TA-1535. An S-9 activation
system was not present. No mutagenic response was detected with or
without S-9 in a standard assay system where dichloromethane was added
directly to plates containing Salmonella strains TA-1535, TA-1537,
TA-1538, TA-98 or TA-100 (Nestman et al., 1980).
Dichloromethane was reported to be mutagenic to Salmonella
typhimurium strain TA-100 when aliquots of 50, 100, 200, 400 and 800
microlitres of the compound were placed in a glass dish in a
desiccator along with plates containing the bacteria. A linear
response of histidine revertants/plate occurred over the entire tested
dose range; the maximum response obtained at 800 microlitres, was
about 10 times background levels (Simmon, 1977).
Dichloromethane was reported to induce mitotic gene convertants,
revertants and recombinants in Saccharomyces cerevisiae strain D-7
grown in log plase and exposed to 157 mm of the test compound for one
hour (Callen et al., 1980). Earlier it was reported that
dichloromethane did not affect the frequency of mitotic recombination
in S. cerevisiae strain D-3 exposed to dichloromethane for four
hours (dose not stated) (Simmon et al., 1977).
No increase in sex-linked recessive lethal mutations was reported
in male offspring of Drosophila melanogaster exposed to ingested or
injected dichloromethane (Abrahamson & Valencia, 1980 as cited in
Science Applications, Inc., 1982).
Dichloromethane was found to cause a weak positive effect on
sister chromatid exchange in V79 Chinese hamster epithelial cells. A
negative effect was found on forward mutation at the HGPRT locus on
V79 and Chinese hamster ovary (CHO) cells. No effect of
dichloromethane on unscheduled DNA synthesis in V79 and human
fibroblasts (AH cells was found. The compound caused an aspecific,
non-persistent inhibition of DNA synthesis in V79 and AH cells, unlike
the persistent effect seen with the positive control, 4-nitroquinoline
oxide (Jongen et al., 1981).
Analytical grade dichloromethane was found to be mutagenic
without S-9 when it was added to exposure chambers containing
S. typhimurium TA-100. Addition of S-9 mixtures, S-100 mixture or
the microsomal fraction from phenobarbitol induced rats increased the
mutagenic response to the compound. The addition of glutathione (GSH)
alone also enhanced the mutagenicity of dichloromethane (Jongen et
al., 1982).
Dichloromethane was reported to increase the frequency at which
primary hamster embryo cells in culture were transformed by SA7 virus
when the cells were incubated in a treatment chamber with an
atmosphere containing 22-72 micrograms/cm3 of dichloromethane (Jongen
et al., 1981).
Special studies on occupational exposure
A group of male workers exposed to work place air containing
methylene chloride for up to 30 years were studied for mortalities as
compared to several control groups. A total of 334 deaths occurred in
the study group. Mortality of the exposed group was consistent with
other industrial workers and there was no significant increase in
deaths from any special causes including the different categories of
malignant neoplasm (Friedlander et al., 1978).
Special studies on renal toxicity
Single i.p. injections of 1330 mg/kg bw to adult male Fischer-334
rats were reported to result in renal proximal tubular degeneration in
both the cortex and outer medula (Kluwe et al., 1982).
Special studies on teratology
Groups of 18-21 female Long Evans rats were exposed to 0 or
4500 ppm (0 or 0.45%) of dichloromethane in air for six hours a day,
seven days a week. Four different treatment regimens were used with
the longest regimen consisting of exposure for three weeks prior to
pregnancy through day 17 of gestation. One group was exposed only
during gestation (up to day 21) a third group was exposed for three
weeks prior to, but not during gestation, while the controls were not
exposed to the test substance for any time period. Dams were
sacrificed on day 21 and foetuses delivered by Caesarian section.
Maternal absolute and relative liver weights were significantly
increased in dosed animals. Foetal body weights were significantly
depressed (by a small amount) in the offspring of animals exposed
during gestation. No effects on embryo toxicity or gross skeletal or
soft tissue anomalies were reported except for a possible increase in
the incidence of rudimentary fourteenth ribs in offspring whose
mothers were exposed to dichloromethane prior to breeding or prior to
breeding and through gestation. However, the report stated that the
effect was not significant if the litter, rather than the foetus was
considered as the experimental unit (Hardin & Manson, 1980).
Behavioural teratology studies were conducted on the offspring of
female rats dosed with dichloromethane according to the protocol of
the preceding study of Hardin & Mansen. No effects on offspring were
noted with regard to growth rate, long-term food or water consumption,
wheel running or avoidance activity. However, offspring of females
exposed to dichloromethane during pregnancy habituated to novel test
environments more slowly than controls (Bornschein et al., 1980).
Groups of at least three pregnant Sprague-Dawley rats were
exposed to 507 ppm (0.0507%) of dichloromethane for one hour on the
twenty-first day of gestation. After exposure the animals were
sacrificed and maternal and foetal blood levels of dichloromethane and
carbon monoxide were measured. Maternal and foetal blood levels of
carbon monoxide did not differ significantly (Anders & Sunram, 1982).
Short-term studies
Groups of 10 male and 10 female Fischer-334 rats were given 0,
125, 250, 500, 750, 1000, 1500 or 2000 mg/kg bw of dichloromethane
five days a week for 13 weeks by gavage in a corn oil vehicle. There
were no compound-related deaths except in high dose females where two
animals died. High-dose males and females exhibited about a 17-20%
reduction in weight gain. These animals also exhibited severe CNS
depression lasting about two hours after receiving each dose. No gross
or microscopic lesion related to the administration of dichloromethane
was reported. A complete set of tissues was evaluated (NTP, 1982).
Groups of five male and five female Fischer-344 rats were
administered 0, 250, 500, 1000, 1500 or 2000 mg/kg of dichloromethane
in a corn oil vehicle by gavage daily for 14 days (continuous dosing
group). Other groups received the same doses five days per week for 12
weeks, and four doses on the third week (intermediate dosing). Severe
depression lasting for one to three hours was noted after dosing at
the 1500 and 2000 mg/kg doses. Mortality was only noted in the
high-dose animals and was most severe (three out of five) in the
continuously dosed females. No deaths were noted in continuously dosed
males and one out of five on the intermittent high-dosed males.
Changes in mean body weight gain were not dose-related, but compared
to controls the most severe decrements occurred at the two highest
doses. No compound related gross pathological changes were noted, nor
were there any microscopic changes noted in the liver, the only organ
so examined (NTP, 1982).
Groups of 10 male and 10 female C57B1/6 mice were administered 0,
500, 1000, 1500, 2000, 2500, 3000 or 3500 mg/kg by gavage in corn oil
vehicle five days per week for 13 weeks, compound related mortality
occurred at doses of 1500 mg/kg or greater in females and 2000 mg/kg
or greater in males, being most severe in the high-dose females where
only two out of 10 females survived. Changes in body weight gain were
difficult to interpret due to lack of a dose response effect. No
compound related gross or microscopic lesions were noted. A complete
set of tissues was evaluated (NTP, 1982).
Groups of five male and five female B6C3F1 mice were given doses
of 0, 500, 1000, 1500, 2000 or 2500 mg/kg of dichloromethane by gavage
as 14 consecutive daily doses (continuous dosing). Other groups of
five male and five female B6C3Fa mice were given the same doses on a
regimen of five administrations per week for two weeks and then four
doses in the third week. No mortality occurred among the females. In
the high dose males two out of five of the continuously and three out
of five of the intermittently dosed males died before the end of the
study. Body weight gain data are very difficult to interpret; between
group variations are large and there is no dose-related trend. No
compound-related histopathology hepatic lesions were noted. The liver
was the only organ examined histopathologically (National Toxicology
Program, 1982).
Comments
In a recent lifetime study in rats, in which methylene chloride
was administered in olive oil, by gavage, numerous deaths occurred,
particularly in the high-dose groups. Although these deaths may have
been caused by gavage errors, it may also have been due to systemic
toxicity of test compound. In this study, neoplastic nodules occurred
in male and female rats with a significant positive trend. Although,
these lesions may progress to carcinomas, the pathological carcinomas
were found only in one vehicle control and one low-dose male and one
high-dose female. There was a significant increase in the incidence of
pancreatic-acinar cell tumours in male rats. However, there are
numerous reports of an increase in pancreatic-acinar cell tumours in
lifetime studies with rats, and this problem is undergoing active
review. The significance of this observation cannot be established at
this time. It is also noted that two batches of methylene chloride
were used in this study, each containing different impurities. In a
similar study in mice, the major lesion reported was hepatocellular
carcinomas. Because of the known wide fluctuations in the background
level of this tumour in mice, no firm conclusions can be drawn on the
significance of this lesion.
In a rat study in which methylene chloride was administered in
the drinking-water at lower doses than those used in the gavage study,
no hepatocellular carcinomas were reported, although there were minor
changes in the livers of test animals, including a dose-related
increased incidence of foci/areas of cell alteration, fatty livers in
the high-dose groups, and a very low incidence of neoplastic nodules
that was not dose-related.
Two inhalation studies in rats, using, technical grade methylene
chloride indicated a compound-related increase in liver lesions
including foci/areas of cellular alterations. One study indicated an
increased incidence of mesenchymal tumours in or around the salivary
glands. In another inhalation study in Golden hamsters, at equivalent
levels of exposure, no effects on salivary glands were observed.
The available data are inadequate for a complete evaluation of
the carcinogenicity of methylene chloride. The mutagenicity data are
inconsistent, and no conclusion can be made on the possible
mutagenicity of methylene chloride.
A study with B6C3F1 mice exposed to methylene chloride in
drinking-water will be completed in 1983. This will permit a more
complete evaluation of the possible carcinogenicity of methylene
chloride by this route. In addition, an inhalation study in rats and
mice is under way, and the results of this study will assist in
resolving questions raised in the previous inhalation study.
EVALUATION
Estimate of acceptable daily intake for man
The previously allocated ADI has been withdrawn.
FURTHER WORK OR INFORMATION BEFORE AN ADI COULD BE ALLOCATED
(1) Results of a lifetime study with B6C3F1 mice exposed to methylene
chloride in drinking-water.
(2) Results of lifetime inhalation studies with rats and mice.
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See Also:
Toxicological Abbreviations