Registration Dossier

Administrative data

Description of key information

Acute oral LD50 in rats was determined to be greater than 1187 but less than 2769 mg/kg bw in an Study performed according to internal company standards (BASF-test) before actual guideline was adopted.

Acute inhalation LD50 in cats was found to be 43700 mg/m³ after 6 -hour exposure.

LD50 after dermal application in rabbits was found to be about 17100 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Test substance applied as 50 % aqueous solution, postobservation period only 7 days
Principles of method if other than guideline:
Study was performed before actual guideline was adopted. BASF-test.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50 %
- Amount of vehicle (if gavage): 3.2 ml/kg

MAXIMUM DOSE VOLUME APPLIED: 6.4 ml/kg
Doses:
2528 mg/kg bw (6.4 ml/kg)
No. of animals per sex per dose:
10 (sex not specified)
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: no data
- Other examinations performed: clinical signs
Key result
Sex:
not specified
Dose descriptor:
LD0
Effect level:
>= 2 528 mg/kg bw
Remarks on result:
other: application as 50% aqueous solution
Mortality:
No mortality occurred.
Clinical signs:
Staggering, narcotic effects.
Body weight:
no data
Gross pathology:
no data
Other findings:
- Potential target organs: CNS
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 187 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Principles of method if other than guideline:
No further details given
GLP compliance:
not specified
Test type:
other: no details reported
Limit test:
no
Species:
cat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
other: no data
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
6 h
Concentrations:
44.69 mg/L (corresponding to 33600 ppm)
No. of animals per sex per dose:
no data
Control animals:
not specified
Key result
Sex:
not specified
Dose descriptor:
LC50
Effect level:
43.68 mg/L air
Exp. duration:
6 h
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
43 700 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Principles of method if other than guideline:
No further details given
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
not specified
Type of coverage:
not specified
Vehicle:
not specified
Duration of exposure:
no data
Doses:
no data
No. of animals per sex per dose:
no data
Control animals:
not specified
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
17 100 mg/kg bw
Remarks on result:
other: corresponding to 20 ml/kg bw according to the authors

No detailed data: LD50 given as 20 mL/kg.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
17 100 mg/kg bw

Additional information

Animal data

Oral:

In rats, LD50 values after single oral administration range from 1187 to 2769 mg/kg bw, depending on the concentration of the aqueous solution used (BASF 1975, concentrations 15 to 35%, not further specified).

In Rhesus monkeys orally dosed with 6000 mg/kg bw, the retina and the optic papilla showed extended oedema, and the pupils were wide and non-responsive. Six of 8 animals exhibited cystic degeneration of the outer retinal granular layer, and in one animal there was evidence of significant demyelinisation of the optic nerve. Histological lesions were seen in the putamen and nucleus caudatus in 3 of 8 animals. All of these effects were most pronounced after early compensation of acidosis using bicarbonate application, because the monkeys generally did not survive those high doses of methanol but after early treatment with bicarbonate (Potts, 1955; Potts et al., 1955).

There was no evidence of marked acidosis in 12 Rhesus monkeys (28 applications) after sublethal doses up to 6000 mg/kg bw. Specifically, there was no hyperventilation, no increase in urinary excretion of organic acids, or shift in serum bicarbonate. Blindness was seen in only one surviving monkey dosed with 9000 mg/kg bw; the effect was transient four days after exposure. The LD50 was between 7000 and 9000 mg/kg bw (Cooper and Felig, 1961).

Inhalation:

In male and female rats, LC50 values of 87.5 mg/L (6 hours) and 128.2 mg/L (4 hours) were determined (BASF, 1980a,b). Clinical signs of toxicity were aqueous secretion of eyes and nose, labored breathing, staggering, apathy, and narcosis.

A similar range of toxicity values is reported for the mouse: LC50 (2.25 h) = approx. 79 mg/L (Von Burg, 1994).

In cats, a LC50 value of approx. 43.7 mg/L was obtained after a 6-hour exposure (Von Burg, 1994). A shorter duration of 4.5 hours led to a LC50 value of 85.4 mg/L (Von Burg, 1994).

Studies in Rhesus monkeys indicate lethal concentrations (% mortality not reported) of 1.3 mg/L (after 41 hours), 13 mg/L (after 18 hours) and 52 mg/L methanol (after 1–4 hours). Blindness associated with optic nerve atrophy was reported. Eventual recovery from this lesion was observed (McCord, 1931; only limited documentation).

Dermal:

Methanol is classified as acute toxic Cat.3 (H301,H311,H331) according to the EU Regulation 1272/2008. Therefore, animal testing regarding acute dermal toxicity is not necessary.

In rabbits, a dermal LD50 of about 17,000 mg/kg bw was found. No further details were reported (Rowe and McCollister, 1981).

Human data:

Due to misuse of methanol in the production of alcoholic beverages oral ingestion is the most frequent route of poisoning, death and blindness from methanol. However, there are also case reports from percutaneous absorption or vapor inhalation having elicited the methanol acute toxic syndrome.

A blood level of 500 mg/L methanol in acutely poisoned patients is generally regarded as an indication for hemodialysis. This blood concentration can transiently be achieved in an adult person (70 kg) by ingestion of 0.4 mL methanol/kg bw (Kavet and Nauss, 1990). Generally in humans, transient central nervous system (CNS) effects appear at blood methanol levels of 200 mg/L and serious ocular symptoms appear above 500 mg/L ranging from mild photophobia, misty or blurred vison to markedly reduced visual acuity and total blindness (Kavet and Nauss, 1990; Dethlefs and Naraqi, 1978). Acute methanol intoxication evolves in a well-defined pattern. First, a mild depression of the CNS occurs which is followed by an asymptomatic latent period commonly lasting 12 to 14 hours. Clinical symptoms include headache, dizziness, nausea and vomiting, abdominal pain, and labored, periodic breathing and mag progress to coma and death from respiratory failure (Kavet and Nauss, 1990).

The minimal acute methanol dose to humans that can result in death is considered to be 300 to 1000 mg/kg by ingestion. Fatalities have occurred in untreated patients with initial methanol blood levels in the range of 1500 to 2000 mg/L (IPCS/WHO, 1997). In general, coma, seizures and prolonged acidosis were poor prognostic signs (Naraqi et al., 1979). Such high and potentially lethal blood methanol levels are less likely to be achieved from inhalation exposure. Exposure to 0.26 mg/L methanol for 4 hours was without significant physiologic effects in human volunteers (Muttray et al., 2001).

In conclusion, there are two dominating acute effects from methanol: blindness and metabolic acidosis. For the latter, formate is considered to be the ultimate toxicant in acute methanol intoxication in humans. Acidosis and ophthalmologic changes are typical effects in primates. They do not occur in rodents or rabbits, which are able to remove formate more efficiently. In these animals, CNS depression, narcosis and death are the leading symptoms of intoxication.Although the mechanism for optic nerve damage from exposure to methanol has not been established, potential mechanisms and the possible role of formate are discussed in section 5.10.3.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Although the lethal dose of methanol is high for most experimental animals (> 2000 mg/kg bw after single oral administration) these data are not employed for classification. The classification is only based upon the experiences in humans and classifies methanol as acutely toxic by oral, dermal and inhalative exposure and, furthermore, as capable of inducing serious irreversible effects upon single exposure by all of these routes. As a result the substance is considered to be classified for acute toxicity category 3: toxic if swallowed; toxic in contact with skin; toxic if inhaled (H301, H311, H331) and STOT single exposure category 1 (oral, dermal, inhalation; H370) under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776