chloromethane; methyl chloride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: acceptable well documented publication which meets basic scientific principles

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Metabolism of Methyl Chloride to Formate in Rats

Author:

Kornbrust, D.J. and Bus J.S.

Year:

1982

Bibliographic source:

Toxicology and Applied Pharmacology 65, 135-143

Reference 2

Reference Type:

secondary source

Title:

Chloromethane CAS: 74-87-3

Author:

OECD SIDS

Year:

2004

Bibliographic source:

SIDS Initial Assessment Report for SIAM 15 ; www.iccahpv.com

Reference 3

Reference Type:

secondary source

Title:

Toxicological review of methyl chloride (CAS No. 74-87-3)

Author:

Greenberg, M. and Riddle, J.

Year:

2001

Bibliographic source:

U.S. Environmental Protection Agency, EPA/635/R01/003

Reference 4

Reference Type:

secondary source

Title:

Methyl Chloride

Author:

Löf, A. et al.

Year:

2000

Bibliographic source:

Concise International Chemical Assessment Document 28

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

Experiment I: Rats were exposed to chloromethane via inhalation (whole body). Exhaled CO2 was collected.
Experiment II: Pre-treatment of rats with nitrous oxide prior to chloromethane treatment (14 C labelled or unlabelled). Exhaled CO2 was collected. Blood and urine were analyzed for formate levels.
Experiment III: Pre-treatment of rats with methotrexate prior to chloromethane treatment (14 C labelled or unlabelled). Exhaled CO2 was collected. Blood and urine were analyzed for formate levels.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Chloromethane

EC Number:

200-817-4

EC Name:

Chloromethane

Cas Number:

74-87-3

Molecular formula:

CH3Cl

IUPAC Name:

chloromethane

Details on test material:

- Name of test material (as cited in study report): methyl chloride
- Physical state: gaseous
- Analytical purity: no data
- Locations of the label (if radiolabelling): 14C

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Administration / exposure

Route of administration:

inhalation: gas

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

single for 3 h

Doses / concentrations

Remarks:

Doses / Concentrations:
Experiment I and II: 4000 ppm or 10000 ppm (8260 mg/m³ or 20650 mg/m³)
Experiment III: 10000 ppm (20650 mg/m³)

No. of animals per sex per dose / concentration:

4-12 rats

Control animals:

yes

Results and discussion

Metabolite characterisation studies

Details on metabolites:

Experiment I: No formate accumulation was observed following exposure to 4000 or 10000 ppm for 3h. The positive control methanol did increase formate formation when administered at a dose of 50 mg/kg bw.

Experiment II: Nitrous oxide:oxygen (1:1) treatment (4 h: 1 h prior to and 3 h during chloromethane exposure) did increase formate formation in blood and urine of chloromethane exposed rats (4000 and 10000 ppm) compared to respective controls. The positive control methanol did increase formate formation when administered at a dose of 10 mg/kg bw to N2O pre-treated rats.

Experiment III: Methotrexate pre-treatment (6 days) also increased formate levels in blood and urine.
The same pre-treatment also inhibited incorporation of 14C into macromolecules.

Pre-treatment with N2O inhibited the incorporation of 14C into acid-insoluble material from liver or kidney by about 60% and increased exhalation of 14C labelled CO2.

The present results provide evidence that chloromethane is metabolized to formate which is further oxidized to CO2 or incorporated into macromolecules via folate-dependent pathways.