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EC number: 204-699-5 | CAS number: 124-41-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose 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
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Methyl alcohol poisoning. II. Development of a model for ocular toxicity in methyl alcohol poisoning using the Rhesus monkey.
- Author:
- Martin-Amat, G., Tephly, T.R., McMartin, K.E., Makar, A.B., Hayreh, M.S., Hayreh, S.S., Baumbach, G., Cancilla, P.
- Year:
- 1 977
- Bibliographic source:
- Arch Ophthalmol 95: 1847-1850
- Reference Type:
- publication
- Title:
- Methanol poisoning: Ocular toxicity produced by formate.
- Author:
- Martin-Amat, G. et al.
- Year:
- 1 978
- Bibliographic source:
- Toxicol Appl Pharmacol 45: 201-208
- Reference Type:
- publication
- Title:
- Methyl alcohol poisoning IV. Alterations of the morphological findings of the retina and optic nerve.
- Author:
- Baumbach, G.L. et al.
- Year:
- 1 977
- Bibliographic source:
- Arch Ophthalmol 95: 1859-1865
- Reference Type:
- publication
- Title:
- Methyl alcohol poisoning.
- Author:
- Hayreh, M.S. et al.
- Year:
- 1 977
- Bibliographic source:
- Arch Ophthalmol 95: 1851-1858
- Reference Type:
- publication
- Title:
- No information
- Author:
- Martin-Amat, G. et al.
- Year:
- 1 977
- Bibliographic source:
- Metab Syst 2: 419-428 (cited in DGMK 1982)
- Reference Type:
- publication
- Title:
- Methanol poisoning I. The role of formic acid in the development of metabolic acidosis in the monkey and the reversal by 4-methylpyrazol.
- Author:
- McMartin, K.E. et al.
- Year:
- 1 975
- Bibliographic source:
- Biochem Med 13: 319-333
Materials and methods
- Principles of method if other than guideline:
- Test model in monkeys for methanol-induced occular toxicity after short-term exposure to characterize the toxicity syndrome and histological manifestations.
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Methanol
- EC Number:
- 200-659-6
- EC Name:
- Methanol
- Cas Number:
- 67-56-1
- Molecular formula:
- CH4O
- IUPAC Name:
- Methyl alcohol
Constituent 1
Test animals
- Species:
- monkey
- Strain:
- other: Macaca mulatta
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 2.6-4.4 kg
Administration / exposure
- Route of administration:
- other: nasogastric tube
- Vehicle:
- water
- Details on oral exposure:
- VEHICLE
- Concentration in vehicle: 20% (w/v)
- Amount of vehicle (if gavage): 10 mL/kg - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- approx. 1.5 to 6 days
- Frequency of treatment:
- variable
Doses / concentrations
- Dose / conc.:
- 2 000 mg/kg bw/day (nominal)
- Remarks:
- initially 2000 mg/kg, thereafter 500 mg/kg at variable frequencies and time points (exception: one animal 1000 mg/kg at 44 and 72 h and 2000 mg/kg at 144 h)
- No. of animals per sex per dose:
- 6 males in total
- Control animals:
- other: internal/same animal prior to treatment
- Details on study design:
- - Dose selection rationale: A high initial dose (2000 mg/kg) was followed by lower doses depending on the animal´s acidotic response in blood. Experience had told (McMartin et al., 1975) that after a single dose of 3000 mg/kg bw, in general, the animals died within 20 to 30 h without demonstrating ocular abnormalities. (Martin-Amat et al., 1977).
- Positive control:
- not applicable
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes (McMartin 1975, 3000 mg/kg)
- Time schedule: Continuously from application until death (approx. 33 h after application)
- Cage side observations included: clinical signs, mortality
DETAILED CLINICAL OBSERVATIONS: Yes: cerebrospinal fluid pressure in cerebellomedullary cistern by cisternal puncture (2 animals)
- Time schedule: not specified
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: one week before and during the course of intoxication, not further specified
- Dose groups that were examined: all animals: stereoscopic color fundus photography, fluorescein fundus angiography, pupillary light reflex,
HAEMATOLOGY: No
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to treatment and throughout the course of the study
- Animals fasted: No data
- How many animals: all
- Parameters examined: blood pH, bicarbonate levels, methyl alcohol, blood formate (cerebrospinal fluid: 2 animals), pO2, pCO2
URINALYSIS: No - Sacrifice and pathology:
- GROSS PATHOLOGY: No
HISTOPATHOLOGY: Yes (light and electron microscopic studies of neuronal tissues and nerve fibres associated with the eyes: retina, optic nerve heads, optic nerves of 2 control and 3 treated animals)
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Under methanol treatment acc. to this test design, formate levels were between min. 7.2 and max. 14.4 mEq/L in blood and 7.9 to 13.9 mEq/L in cerebrospinal fluid, blood bicarbonate min. 4.0 and max. 10.2 mEq/L, and blood pH min. 7.13 and max. 7.28. Methanol levels ranged from 1540 to 2840 mg/L (Martin-Amat et al., 1977).
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The only detectable ocular change was optic disc edema (of the optic papilla). The primary sites of ocular injury were the optic nerve heads and the anterior segment of the optic nerve rather than the retinal ganglion cells themselves. In all eyes with optic disc changes, pupils were dilated and reacted poorly to light.
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- All six animals developed fundus changes at the head of the optic nerve (optic disc) within 43 to 171 h after methanol ingestion, expressed as intraaxonal swellings (Hayreh et al, 1977). Electronmicroscopic studies revealed swelling of the nerve fibers with an accumulation/clustering of swollen mitochondria in the optic nerve head being maximally in the lamina cribrosa region. Furthermore, in the retrolaminar and intraorbital optic nerve, swelling of astrocytes was prominent as well as swelling of the cytoplasm of the oligodendroglial cytoplasm in contact with the axons (Baumbach et al., 1977). Alterations were not observed in the retina itself: the ganglion cells of the retina were intact with only minimal swellings of the mitochondria and loss of cristae. But these findings were also present in the control tissue (Baumbach et al., 1977).
- Histopathological findings: neoplastic:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 2 000 mg/kg bw/day (nominal)
- System:
- eye
- Organ:
- other: optic nerve
- Treatment related:
- yes
Applicant's summary and conclusion
- Conclusions:
- While acute methanol toxicity in monkeys (after a single dose) does not yield ocular signs, repeated dosing succeeded in producing ocular lesions (Martin-Amat et al, 1977). The only detectable ocular change was optic disc edema (of the optic papilla) which was similar to that seen in raised intracranial pressure in humans, but without this pressure after methanol (Hayreh et al, 1977). The primary sites of ocular injury were the optic nerve heads and the anterior segment of the optic nerve rather than the retinal ganglion cells themselves. It appears that interference with oxidative phosphorylation causes mitochondrial damage, thus disruption of active axoplasmic flow in the retrolaminar optic nerve (Baumbach et al., 1977; Hayreh et al., 1977). [note: In humans it has been hypothesized that optic atrophy, which often follows acute methanol intoxication, is secondary to injury of the retinal ganglion cells.]. Mechanistically, there is a close causal relationship between the prolonged increase in formic acid from methanol and the development of optic edema. Similar effects can be produced by intravenous administration of formate without acidosis (Martin-Amat et al., 1978).
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