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EC number: 201-185-2 | CAS number: 79-20-9
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- 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:
- European Union Risk Assessment Report methyl acetate
- Author:
- European Commission - JRC - ECB
- Year:
- 2 003
- Bibliographic source:
- Office for Official Publications of the European Communities, Luxembourg
- Reference Type:
- publication
- Title:
- Toxicological Research of Methanol as a Fuel for Power Station, Summary Report on Tests with Monkeys, Rats and Mice
- Author:
- NEDO
- Year:
- 1 987
- Bibliographic source:
- New Energy Development Organization, Tokyo, 1987
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- yes
- Remarks:
- limited documentation; copulation time was too long (21 days); not all parameters mentioned in the guideline were investigated
- GLP compliance:
- not specified
- 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:
- methanol
- Details on test material:
- TS-Freetext:
Methanol, reagent special grade from Junsei Chemicals Co.,
<1 ppm vinyl chloride, <3 ppm formaldehyde
------------------
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan Inc.
- Age at study initiation: 8 weeks
- Diet: Solid Chow for rat (CRF-1, Charles River Japn Inc.)
- Water: sterilised and filtrated water (ad libitum)
- Acclimation period: 10 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 2 °C
- Humidity (%): 55 ± 15 %
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- inhalation
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: multi-stage inhalation chamber (Hazleton 1000 exposure chamber)
- Temperature, humidity in air chamber: 24 ± 2 °C; 55 ± 5 %
TEST ATMOSPHERE
- Nominal exposure levels were prepared by generating methanol gas and then mixing it with fresh air.
- A methanol gas analyser measured the concentration in the chamber. - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: 21 d
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Other: The pairs without evidence of insemination within 21 d were again cohabited with untreated animals (2nd mating) to determine the fertility of each animal, in this case without exposure (p.186). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical concentration values of methanol were close to nominal ones (the monthly variation remained less than 5 %).
- Duration of treatment / exposure:
- F0: 103 -108 d
F1: 61 -62 d and 145 -153 d
F2: 54 -56 d
further informations see "any other information on materials and methods" - Frequency of treatment:
- continuously
- Details on study schedule:
- - F1 parental animals not mated until 12 weeks after selected from the F1 litters.
- Female F1 animals were examined for sexual cycle at 12-weeks or thereafter and mated with males of the same group.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.013 mg/L air
- Remarks:
- corresponding to 10 ppm
- Dose / conc.:
- 0.13 mg/L air
- Remarks:
- corresponding to 100 ppm
- Dose / conc.:
- 1.3 mg/L air
- Remarks:
- corresponding to 1000 ppm
- No. of animals per sex per dose:
- 30 (F0 generation)
Additionally, 15 animals were reared for a second mating - Control animals:
- yes, concurrent no treatment
Examinations
- Parental animals: Observations and examinations:
- Observations of F0 and F1 parental animals.
CAGE SIDE OBSERVATIONS:
- clinical signs, mortality, any sign of abortion and premature delivery
- Time schedule: at least once a day, 5 days a week
BODY WEIGHT:
- Time schedule for examinations: animals were weighed weekly: day 0, 7, 14 and 20 of gestation and day 0, 4, 7, 14 and 21 of delivery
FOOD AND WATER CONSUMPTION::
- consumption measured by cage (on the same days as body weight measurements)
OTHER:
- Generally sexual cycle, mating time, fertility, pregnancy rate were documented. During the lactation period, maternal animals were observed for nursing behavior including lactation, nest building and presence/absence of pup-eating. - Sperm parameters (parental animals):
- Histological examination of morphology of sperms was not included.
- Litter observations:
- Observations of F1 and F2 litters.
Litters were examined on the day of birth for live pups, dead pups, sex and any external abnormalities. The observations were done daily until weaning and thereafter 5 days a week.
Each litter was weighed on day 0 and 4 (before reduction) of birth by sex and respective mean value calculated. After adjustment of litter size, pups were weighed individually on day 4, 7, 14 and 21. From weaning to week 14 of birth, the measurements were done weekly.
All surviving pups were observed for post-natal morphological differentiation indices: pinna unfolding, eruption of incisors, open eyes, descensus testis (males), vagina opening (females).
As for movement function test, all surviving pups after adjustment of litter size were tested for righting on a surface, ipsilateral flexor reflex, pinna reflex, auricular startle response, visual recognition response, pain response, corneal reflex and suspension abililty on a particular day before weaning. Also emotional tests, learning ability tests, and movement coordination tests were included.
In 9-week old F1 pups, blood methanol was measured, but not formate. - Postmortem examinations (parental animals):
- Examinations of F0 and F1 parental animals.
After mating all males were necropsied, and testes, epididymis, seminal vesicle and postate gland were removed and preserved.
After 2 weeks of rearing, the females at the 2nd mating were necropsied and examined for pregnancy status. After termination of mating, the not inseminated females were necropsied and the ovary, uterus and bagina were preserved.
21 days after delivery, all dams were necropsied and examined for implantation. The vagina, uterus and ovary were preserved.
Any organ with any abnormality was subjected to a histopathological examination, if necessary.
26 days after evidence of insemination, females which had not yet delivered were necropsied and subjected to the same examinations as the above. - Postmortem examinations (offspring):
- Examinations of F0 and F1 litters.
After termination of movement function tests, pups were sacrificed and necropsied.
The pups which were selected for examination and not used for the movement function test were necropsied on a day of the same age at 8 weeks old or thereafter and principal organs were weighed. - Statistics:
- All data obtained were analysed by t-test, Fischer´s exact test, U-test of Mann-Whitney or Armitage´s chi²-test.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- None of the fertility indices including sexual cycle, days needed for insemination, insemination rate and pregnancy rate showed statistically significant differences.
No abnormalities were observed in findings on delivery and nursing behavior and necropsy data of F0 animals.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 1.3 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive performance
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: P1 (second parental generation)
General toxicity (P1)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
Reproductive function / performance (P1)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- not specified
Effect levels (P1)
- Remarks on result:
- not measured/tested
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In male pups of the 1.3 mg/L group, post-natal morphological differentiation appeared to be influenced with respect to the descensus tests occurring 0.5 to 1 d earlier (see same effect in F2 generation): This time-dependent parameter was evaluated by relating the completion of downward migration of the testes (final length of the gubernaculum reached) to the post-natal body-weight gain (The more reliable body length was not available):
In the F1 pups derived from the 1.3 mg/L group (108 males), this process was completed within 16 through 20 post-natal days with the climax at day 17 and 18 (32 and 39 %, respectively), while in the respective control (113 males), descent was complete from 16 through 21 days with the maximum at day 19 (32 %), but also relatively high percentages on the days before and after: day 18 (22%), day 17 (19%), day 20 (18%). - Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- 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
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Description (incidence and severity):
- None of the fertility indices including sexual cycle, mating time, fertility and pregnancy rate showed a significant difference from untreated F1 controls.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Absolute and relative brain weights were significantly lowered in the high-dose groups of either sex at an age of 8 and 16 weeks. This was still found in females necropsied after 24 weeks. Also other organs showed slight shifts in weights: thymus, pituitary (lower), heart, lung, liver (higher).
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathological examination was performed on organs containing those with significant difference in weight for the high-dose group (1000 ppm): brain, pituitary, thyroid, thymus, heart and liver.
For the liver: infiltration of leukocytes was observed in high incidence (63.9 ~ 91.7%) but an intergroup difference was not observed.
For the thyroid: fetal residues were observed in relatively high incidence (33.3 ~ 75.0%) but intergroup difference was not noted.
The remaining organs did not show any abnormality.
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- There were no significant differences in functional tests (movement, emotion, learning) as compared to control or the other groups.
Effect levels (F1)
open allclose all
- Key result
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- 0.13 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- other: reproductive parameter
- Key result
- Dose descriptor:
- LOAEC
- Generation:
- F1
- Effect level:
- 1.3 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- other: reproductive parameter
Target system / organ toxicity (F1)
- Critical effects observed:
- no
Results: F2 generation
General toxicity (F2)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- As in F1 males, an apparently dose-related earlier descensus testis was noted after 1.3 mg/L exposure: F2 (94 males) on day 16 (42%), day 17 (40%), day 18 (15%) vs. control (91 males) on day 16 (10%), day 17 (39%), day 18 (31%), day 19 (14%) (p. 200).After 0.13 mg/L, "descensus testis" in male F2-progeny was about 0.5 d earlier than in male control F2 pups.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Organ weights showed similar tendencies as found in the F1-generation.
At the 8-weeks-old necropsy, the brain, pituitary gland and thymus weights showed significantly lower values and the lung and thyroid weights slightly lower in high-dose group (1,000 ppm) males. As for organ/body weight ratio, the pituitary showed a significantly lower value, and the heart, liver and kidneys significantly higher values.
In the high-dose group (1,000 ppm), females, similar to males, showed significantly lower brain, pituitary and thymus weight values and the thyroid weight was slightly lower. As for organ/body weight ratio, a significant decrease was noted for the thymus. The pituitary and thyroid glands showed slightly lower values but the differences were not significant. In addition, a significant increase was noted for the liver. - Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Developmental neurotoxicity (F2)
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- As for the results of the movement function test, emotional test (open field test) and learning ability test (pole-climbing test) and movement coordination test, there were no significant differences in any exposure group.
Effect levels (F2)
open allclose all
- Key result
- Dose descriptor:
- NOAEC
- Generation:
- F2
- Effect level:
- 0.13 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- other: reproductive parameter
- Key result
- Dose descriptor:
- LOAEC
- Generation:
- F2
- Effect level:
- 1.3 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- other: reproductive parameter
Target system / organ toxicity (F2)
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
Blood levels of methanol measured in the F1-offsprings (age 9 weeks) (NEDO, 1987, p. 191):
controls (baseline): approx. 2 - 3 mg/L
0.013 mg/L methanol: approx. 3 - 3.5 mg/L
0.13 mg/L: approx. 1 - 4.2 mg/L
1.3 mg/L: approx. 53 (males)-100 (females) mg/L
There are no data on formate.
Note: Exposure per day was 20 h, which implies that prolonged steady-state blood levels were reached which even may have been higher
than in studies using the same exposure concentration, but shorter exposure times.
Applicant's summary and conclusion
- Conclusions:
- The 2-generation whole body inhalation reproductive study in which rats were exposed for 19-20 hours/day, decreased brain weights in the first and second generation offspring (F1, F2), but without noticeable histological changes and functional impairments. This results in a NOAEL of 0.13 mg/L.
No impairment of fertility and reproductive performance was found in male and female rats (parent and daughter generation) exposed to continuously high doses of methanol.
Thus, from the overall results of this study a NOAEC/fertility of 1,000 ppm (1,300 mg/m3) can be derived for methanol for continuous inhalatory exposure. - Executive summary:
In this two-generation reproduction test of methanol inhalation in rats, rats were exposed for 19-20 hours/day (NEDO, 1987).
Blood levels of methanol for the low-dose (10 ppm) and mid-dose (100 ppm) groups were almost comparable to the control group. For the high-dose group (1,000 ppm), however, it was 53 ppm and 99 ppm for males and females, respectively.
No treatment-related alterations in general observations and reproductive parameters were found.
None of the fertility indices including sexual cycle, days needed for insemination, insemination rate and pregnancy rate showed statistically significant differences.
There were no differences for body weight, food consumption and water consumption during gestation and lactation period, either.
No abnormalities were observed in findings on delivery and nursing behaviour and necropsy data of F0 animals.
No firm conclusions can be drawn about fertility of either sex, as the copulation time of 21 days was comfortably long for successful insemination and gametogenesis was not considered.
In the F1 and F2 progeny (both sexes), no histological changes and no effects on testes or ovaries were reported.
However, a decrease in brain weights was evident at 1.3 mg/L methanol, but without noticeable histological changes and functional impairments. However, no quantitative data and statistical level were documented for organ weights.
The meaning of an apparent shift of testis descent in male offspring in relation to body weight development of the pups in the two following generations is described in this study and considered a significant difference from untreated controls. Furthermore, it is obvious that this parameter showed considerable variation also between the control groups of both generations.
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