METHYLENE CHLORIDE
Explanation
The available biological data relating to both animal and human
exposure to dichloromethane were evaluated by the Joint FAO/WHO Expert
Committee on Food Additives in 1970. Since then the following data
have been published.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Male and female Sprague-Dawley rats (120-400 g/bw) were given
single i.p. doses in corn oil, ranging from 412 to 930 mg/kg
14C-labelled dichloromethane. Immediately following dosing the rats
were placed in a metabolism chamber which enabled the collection of
expired air, faeces and urine.
Animals were killed at 2, 8 and 24 hours after the administration
of the labelled dichloromethane. Analysis of excreta and body tissues
indicated that at 24 h most of the dose (91.5%) was excreted unchanged
in the expired air, 2% was eliminated as carbon monoxide and 3% as
carbon dioxide. There was evidence that more than 75% of the dose was
eliminated in the first 2 h after administration. There was no support
for the theory that dichloromethane is metabolized to formaldehyde
(DiVincenzo & Hamilton, 1975).
Further evidence for the metabolism of dichloromethane to carbon
monoxide and the subsequent formation of elevated carboxyhaemoglobin
levels in the blood was obtained from a study in which male Sprague-
Dawley rats were exposed to concentrations of 1935 mg/m3
14C-labelled solvent in the air for 1 h. It was also shown in this
experiment that the dichloromethane is distributed throughout the body
tissues and its concentrations falls dramatically upon cessation of
exposure (Carlsson & Hultengren, 1975).
Roth et al. (1975) showed that exposure of rabbits of
dichloromethane in the atmosphere resulted in an increase in the
percentage of carboxyhaemoglobin (COHb) in blood. Extended exposure to
high levels of dichloromethane resulted in COHb percentages which
reached a plateau. This was thought to be the result of saturating the
metabolic pathways of the solvent coupled with the elimination rate of
carbon monoxide via the lungs.
Exposure of male Wistar rats (80-100 g/bw) to 500 or 5000 ppm
dichloromethane in air, 5 h/day for 10 days resulted in slight
increases of cytochrome P450 at the 500 ppm level and both cytochrome
P450 and aminopyrine demethylase activity at the 5000 ppm level
(Norpoth et al., 1974).
TOXICOLOGICAL STUDIES
Teratology study
Groups of 13 pregnant Swiss Webster mice and 19 pregnant Sprague-
Dawley rats were exposed to 1250 ppm dichloromethane in the
atmosphere, 7 h/day on days 6-15 of gestation. The young were removed
by Caesarian section and examined for soft tissue and skeletal
abnormalities. No significant material or foetal toxicity attributable
to treatment was reported and there was no teratogenic potential in
either species on the part of the solvent at this exposure level. The
COHb content of blood was elevated in both mice and rats exposed to
dichloromethane (Schwetz et al., 1975).
Human data
The concentration of dichloromethane was determined in the
alveolar air and blood of 14 subjects exposed to 870 and 1740 mg/m3
of the solvent in air during periods of rest and physical exercise.
The uptake of the solvent was found to vary from 55% of the amount
supplied at rest to 30% of the amount supplied during exercise. The
percentage of COHb in the blood increased with increasing exposure and
for a period after exposure. At the highest solvent exposure a level
of 5.5% COHb was recorded (Astrand et al., 1975).
Although exposure of human subjects to a level of 500 ppm
CH2CL2 in the atmosphere for periods of up to three hours was
reported to result in lapses of attention and decreased manual
performance (Winneke & Fodor, 1976), in a similar experiment in which
14 male subjects were exposed to levels of up to 1000 ppm
dichloromethane in the air for two hours, no significant impairment of
reaction time, short-term memory or numerical ability was reported
(Gamberale et al., 1975).
Studies of the COHb level were made of seven subjects who were
exposed to solvent concentrations between 245 and 471 ppm in their
working environment for eight hours every day. The results indicated
that the % COHb rose from a mean of 4.5% immediately before exposure
to a maximum of 9.0% after eight hours exposure then falling
exponentially 4.5% by the start of work on the following day. The
24-hours time-weighted average was found to be 7.3%.
Comments
There are no adequate short- or long-term oral toxicity studies
with this solvent. However, the available data indicate that the
metabolism and excretion pattern of methylene chloride are similar
regardless of route of administration. In animals and man the majority
of the dose is excreted unchanged in the expired air, a small
percentage being converted to carbon monoxide which then binds with
haemoglobin and results in an elevated COHb concentration in the
blood.
High dosage produces narcosis but a long history of industrial
exposure indicates no major acute toxicity. The long-term inhalation
data were available in summary form and there was no way of judging
the precise solvent intake in the test animals. However, in short-term
studies food extracted with the solvent appeared to be non-toxic.
The use of this solvent should be restricted to that determined
by good manufacturing practice, which is expected to result in minimal
residues unlikely to have any significant toxicological effect.
However, residues from each application should be judged individually.
EVALUATION
Estimate of temporary acceptable daily intake for man
0-0.5 mg/kg bw (residues from each application should be judged
individually).
FURTHER WORK OR INFORMATION
Required by 1983.
Data from long-term oral studies in two rodent species.
REFERENCES
Astrand. I., Ovrum, P. & Carlsson, A. (1975) Exposure to methylene
chloride. 1. Its concentration in alveolar air and blood during
rest and exercise and its metabolism, Scand. J. Work. Environ.
Hlth, 1, 78
Carlsson, A. & Hultengren, M. (1975) Exposure to methylene chloride.
III. Metabolism of 14C-labelled methylene chloride in rat,
Scand. J. Work. Environ. Hlth, 1, 104
DiVicenzo, G. D. & Hamilton, M. L. (1975) Fate and disposition of
(14C) methylene chloride in the rat, Toxicol. Appl.
Pharmacol., 32, 385
Gamberale, F., Annwall, G. & Hultengren, M. (1975) Exposure to
methylene chloride. II. Psychological functions, Scand. J. Work.
Environ. Hlth, 1, 95
Norpoth, K. et al. (1974) Induction of microsomal enzymes in the rat
liver by inhalation of hydrocarbon solvents, Int. Arch.
Arbeitsmed., 33, 315
Ratney, R. S., Wegman, D. H. & Elkins, H. B. (1974) In vivo conversion
of methylene chloride to carbon monoxide, Arch. Environ. Hlth,
28, 223
Roth, R. P. et al. (1975) Dichloromethane inhalation, carboxy-
haemoglobin concentrations, and drug metabolizing enzymes in
rabbits, Toxicol. Appl. Pharmacol., 33, 427
Schwetz, B. A., Leong, B. K. J. & Gehring, P. J. (1975) The effect of
maternally inhaled trichlorethylene, perchloroethylene, methyl
chloroform, and methylene chloride on embryonal and foetal
development in mice and rats, Toxicol. Appl. Pharmacol., 32,
84
Winneke G. & Fodor, G. G. (1976) Dichloromethane produces narcotic
effect, Occ. Hlth Safety, 45, 34