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Administrative data

Endpoint:
additional toxicological information
Type of information:
other: reviews
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data from collection of data (Reviews). Peer-reviewed data.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Methanol
Author:
DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area
Year:
1999
Bibliographic source:
In: Occupational Toxicants: Critical Data Evaluation for MAK Values and Classification of Carcinogens (Greim, H., ed.), Wiley-VCH
Reference Type:
publication
Title:
Methanol, Environmental Health Criteria 196
Author:
IPCS/WHO
Year:
1997
Bibliographic source:
International Programme on Chemical Safety, World Health Organisation Geneva, 1997
Reference Type:
review article or handbook
Title:
The toxicity of inhaled methanol vapors.
Author:
Kavet, R. and Nauss, K.M.
Year:
1990
Bibliographic source:
Critical Reviews in Toxicology 21(1): 21-50
Reference Type:
publication
Title:
NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Methanol.
Author:
National Toxicology Program
Year:
2003
Bibliographic source:
NIH Publication No. 03-4478, Sept 2003

Materials and methods

Type of study / information:
Collection of data from various publications and reviews summarizing information on toxicokinetics, acute and repeated dose toxicity, developmental toxiciy and exposure data (occupational and non-occupational) of methanol in humans, non-human primates and rodents, being the basis for the assessment of MAK and BAT values.
Principles of method if other than guideline:
Information on methanol metabolism and toxicity from various publications was taken together in these reviews, two of which, among others, document the assessment of MAK and BAT values.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
Methanol
EC Number:
200-659-6
EC Name:
Methanol
Cas Number:
67-56-1
Molecular formula:
CH4O
IUPAC Name:
methanol
Details on test material:
- Name of test material (as cited in study report): methanol
- Analytical purity: no data

Results and discussion

Any other information on results incl. tables

Occurrence: Methanol is a natural occurring chemical produced in the human body and found in expired air and body fluids. Environmental exposures can occur through air, water, or food, which is the primary source of human exposure. Methanol occurs naturally in fresh fruits and vegetables, but people are also exposed by two direct food additives, aspartame and dimethyl dicarbonate (DMDC), which are metabolized to produce methanol. Methanol further occurs in alcoholic beverages, tobacco, and motor vehicle fuels.

Metabolism: The biological transformation takes place in three steps: 1. Oxidation to formaldehyde by alcohol dehydrogenase of the liver; 2. Oxidation to formic acid by formaldehyde dehydrogenase in the liver; 3. Oxidation to carbon dioxide and water with contribution of the co-enzyme tetrahydrofolic acid. With primates the folic acid content is low, which results in the formation of formic acid observed during methanol intoxication, rendering primates especially sensitive to methanol.

Kinetics: Methanol can enter the human organism via three ways: in liquid state by oral or percutaneous uptake as well as in vapour form via the lungs (pulmonary uptake). Inhalation of the vapour and skin contact are the most important routes for occupational exposure, otherwise oral uptake is the most frequent way of methanol intoxication (confusion with ethanol, ignorance, or suicide). The total amount of methanol retained after pulmonary uptake depends on the duration of exposure and respiratory minute volume. In a study with 5 volunteers a mean pulmonary retention of 57.7 % was found. In another study an average methanol absorption rate of 0.192 mg/cm²/min was determined in vivo for human skin.

Methanol distributes to all tissues very quickly, independent of the method of application. After inhalational uptake methanol concentrations between 1 and 10 mg/dL in the blood and 2.2 and 1.1 times higher concentrations in the urine were found, respectively. Pulmonary excretion of unchanged methanol amounted with oral application to 22% and with epicutaneous application 16% of the dose taken in (in both cases over a time span of 5 h, half-life 1.5 h) This half-life was also confirmed for inhalational exposure. Urinary excretion of unchanged methanol is considerably lower, ranging from 1.3% of the applied dose down to 0.31 and 0.13 % of the orally and epicutaneously applied doses, respectively, depending on the author.

Elimination of methanol follows a first order kinetics after low doses and low plasma levels, and this also applies to methanol levels probably reached after occupational exposure. With uptake of higher, acutely toxic doses the methanol elimination follows kinetics of zero order, i. e. with a constant speed independent of the the concentration in the blood, when the capacity of enzymatically controlled elimination is exceeded. Formaldehyde is neither detectable in the blood nor in the urine, due to its extremely short half-life. The formic acid formed from methanol is only excreted to a small extent (about 1.0% of the applied methanol dose) via the urine, the greatest part is eliminated as CO2 in the expired air. The limiting factor for the metabolic elimination of formic acid is the folic acid content, which is low in humans. Thus, with high methanol exposure the formic acid accumulates in the organism with subsequent effects.

Toxicity: The impairment of vision as well as other CNS structures, typically observed with methanol intoxication, has to be attributed to the formation of formic acid, the primary toxic agent, in contrast to the narcotic effect, which depends on the methanol itself. The symptoms of methanol intoxication are independent of the route of uptake. It is characterized by 3 stages: 1. narcotic effect (due to methanol itself); 2. latent period (about 10 - 48 h); 3. manifestation of the intoxication symptoms (probably due to formic acid).

Stage 3 begins with unspecific disturbances in the general state of health (headache, dizziness, nausea etc.). With increase of the formic acid concentration in the blood and the resulting metabolic acidosis there can be disturbances of consciousness up to severe coma andpossibly death. The characteristic initial symptom with regard to the eyes is blurred vision, development of a scotoma or a central scotoma with corresponding losses of the field of vision. Finally transitory or irreversible blindness (wide, fixed pupils) can occur. The ophthalmoscopic findings range from hyperaemia to oedema of the optic disk to (often only temporary) pallor of the disk as signs of optic atrophy. Further CNS impairments have been described, in particular extrapyramidal symptoms similar to Parkinson's disease due to a bilateral putamen necrosis.

Based on the reported findings, a MAK value of 200 ppm (0.27 mg/L) and a BAT value of 30 mg/L urine were derived.

Applicant's summary and conclusion

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