479. Methyl chloride (WHO Food Additives Series 14)

<HTML> <HEAD> <META HTTP-EQUIV="Content-Type" CONTENT="text/html; charset=iso-8859-1"> <TITLE>479. Methyl chloride (WHO Food Additives Series 14)</TITLE> </HEAD> <BODY BGCOLOR="#FFFFFF"> <A HREF="http://www.inchem.org"><IMG SRC="../../inchemhead.jpg" WIDTH="630" HEIGHT="65" BORDER="0" ALT="IPCS INCHEM Home"></A> <PRE> <A NAME = "PartTitle:METHYLENE CHLORIDE"></A>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 <A NAME = "SectionTitle:BIOCHEMICAL ASPECTS"></A>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). <A NAME = "EndSectionTitle:BIOCHEMICAL ASPECTS"></A><A NAME = "SectionTitle:TOXICOLOGICAL STUDIES"></A>TOXICOLOGICAL STUDIES <A NAME = "SubSectionTitle:Teratology study"></A>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). <A NAME = ":Teratology study"></A><A NAME = "SubSectionTitle:Human data"></A>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%. <A NAME = ":Human data"></A><A NAME = "SubSectionTitle:Comments"></A>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. <A NAME = ":Comments"></A><A NAME = "EndSectionTitle:TOXICOLOGICAL STUDIES"></A><A NAME = "SectionTitle:EVALUATION"></A>EVALUATION Estimate of temporary acceptable daily intake for man 0-0.5 mg/kg bw (residues from each application should be judged individually). <A NAME = "EndSectionTitle:EVALUATION"></A><A NAME = "SectionTitle:FURTHER WORK OR INFORMATION"></A>FURTHER WORK OR INFORMATION Required by 1983. Data from long-term oral studies in two rodent species. <A NAME = "EndSectionTitle:FURTHER WORK OR INFORMATION"></A><A NAME = "EndPartTitle:METHYLENE CHLORIDE"></A><A NAME = "PartTitle:REFERENCES"></A>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 <A NAME = "EndPartTitle:REFERENCES"></A> </PRE> <script src="/scripts/google_analytics.js" type="text/javascript"></script> </BODY> <PRE> </PRE> <PRE> See Also: <A HREF="../../eintro/eintro/abreviat.htm">Toxicological Abbreviations</A> <A HREF="../../icsc/icsc/eics0419.htm">Methyl chloride (ICSC)</A> <A HREF="../../pims/chemical/metchlor.htm">Methyl chloride (PIM 339)</A> <A HREF="../../cicads/cicads/cicad28.htm">Methyl chloride (CICADS 28, 2001)</A> <A HREF="../../iarc/vol71/026-methylchloride.html">Methyl Chloride (IARC Summary & Evaluation, Volume 71, 1999)</A> </PRE> </HTML>

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479. Methyl chloride (WHO Food Additives Series 14)