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Diss Factsheets

Toxicological information

Genetic toxicity: in vivo

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Administrative data

in vivo mammalian cell study: DNA damage and/or repair
Type of genotoxicity: DNA damage and/or repair
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: scientifically acceptable publication

Data source

Reference Type:
Methanol Exposure Does Not Lead to Accumulation of Oxidative DNA Damage in Bone Marrow and Spleen of Mice, Rabbits or Primates.
McCallum, G.P., Siu, M., Ondovcik, S.L., Sweeting, J.N., Wells, P.G.
Bibliographic source:
Molecular Carcinogenesis 9999: 1 - 10

Materials and methods

Principles of method if other than guideline:
This study was performed to determine whether MeOH could indirectly DNA damage via ROS-mediated mechanism. Animals (mice, rabbits and monkeys) were treated with either once or for 15 days with 2.0 g/kg MeOH i.p.. Oxidative DNA damage was observed by measuring 8-oxo-2'-deoxyguanosine. Lipid peroxidation in bone marrow and spleen homogenates was determined by measuring the Ievels of HNE-His protein adducts.
GLP compliance:
not specified
Type of assay:
other: oxidative DNA damage

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): MeOH
- Physical state: liquid
- Analytical purity: HPLC grade

Test animals

other: mouse, rabbit, monkey
other: CD-1, New Zealand white, cynomolgus
Details on test animals or test system and environmental conditions:
- Source: mice, rabbits and monkeys: Charles River Laboratories
- Age at study initiation: mice: 9 - 13 weeks; rabbits: 5 months; monkeys: 3.4 - 5.7 years
- Weight at study initiation: rabbits: 3.25 - 3.75 kg, monkeys: 2.8 - 4.8 kg
- Diet: mice: rodent chow ad libitum; rabbit: standard high-fiber rabbit chow; monkeys: certified primate chow diet (# 5048) from Purina Mills (St. Louis, MO) supplemented with fruit or vegetables 2-3 times weekly
- Water: mice, rabbit and monkeys: ad libitum
- Acclimation period: monkeys: two weeks

- Temperature (°C): mice and rabbits: 20°C; monkeys: 18 - 29°C
- Humidity (%): mice: 50%, rabbits: 60%
- Photoperiod (hrs dark / hrs light): mice: 10/14; rabbits and monkeys: 12/12

Administration / exposure

Route of administration:
- Vehicle(s)/solvent(s) used: saline
Details on exposure:
Mice: Drugs were administered via intraperitoneal (ip) injection using a 26 gauge (G) 3/8 needle.
Rabbits: by ip injection usinga 23 G needle
monkeys: were lightly sedated with ketamine (ca. 5 - 10 mg/kg) for dose administration and then administered MeOH (2g/kg bw; 20% [w/v] in sterile saline) or a saline vehicle by ip injection using a 22G needle.
Duration of treatment / exposure:
single or 15 consecutive days
Frequency of treatment:
Post exposure period:
6 hours or 15 days
Doses / concentrations
Doses / Concentrations:
2 g/kg bw
nominal conc.
No. of animals per sex per dose:
Three rabbits and primates were used in each treatment group. Four and five mice were used in each group for the acute and chronic studies, respectively.
Control animals:
yes, concurrent vehicle
Positive control(s):
- Justification for choice of positive control(s): is a known renal carcinogen
- Route of administration: i.p.
- Doses / concentrations: 100 mg/kg bw at a fixed volume of 0.1 mL/10g bw


Tissues and cell types examined:
DNA from spleen and bone marrow
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: The effect of a Iimit dose of 2.0 g/kg bw MeOH based on guidelines established for the comet assay developed in accordance with the in vivo genetic toxicology guidelines of the Organization for Econornic Co-operation and Development (OECD) were studied.

METHOD OF ANALYSIS: DNA was isolated using DNAzol, a novel guanidine-detergent lysing solution that hydrolyzes RNA and allows for the selective precipitation of DNA from cell lysates. 8-oxodG and dG were analysed via HPLC system. Lipid peroxidation in bone marrow and spleen homogenates was determined by measuring the Ievels of HNE-His protein adducts.
Statistical analysis was performed using GraphPad Instat Version 3.05 (GraphPad Software, lnc., San Diego, CA). Experiments comparing two groups were analyzed by unpaired t tests and multiple comparisons were anaJyzed by one-way ANOVA followed by a Tukey post-test. The Ievel of significance was set at P<0.05.

Results and discussion

Test results
not examined
Vehicle controls validity:
Negative controls validity:
not examined
Positive controls validity:
Additional information on results:
No increase in oxidative DNA damage was observed in bone marrow or spleen at 6 h following exposure to MeOH (2.0g/kg bw ip) in mice, rabbits,
or primates. Similarly, no increase in oxidative DNA damage was observed in bone marrow or spleen 24 h following exposure to a single dose of MeOH (2.0g/kg bw ip), or following 15 consecutive daily doses of 2.0g/kg bw ip MeOH in CD-1 mice. No increase in HNE-His protein adducts was observed in bone marrow or spleen at 6 h following exposure to MeOH (2.0 g/kg bw ip) in primates. MeOH exposure (2.0 g/kg bw ip) increased HNE-His protein adducts 1.4-fold 6 h post-dose in bone marrow of mice, with adduct Ievels returning to basal values within 24 h. No increases in HNE-His protein adducts were observed in spleen of mice or bone marrow of rabbits following MeOH exposure (2.0 g/kg bw ip). MeOH exposure (2.0 g/kg bw ip) increased HNE-His protein adducts 1.5-fold 6 h post-dose in spleen of rabbits.

Applicant's summary and conclusion

Interpretation of results (migrated information): negative
Taken together these observations suggest that it is unlikely that exposure to MeOH would initiate Iymphomas, particularly in humans, via formation
of mutagenic oxidative DNA lesions.