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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
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
Remarks:
documentation limited

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Toxicological Research of Methanol as a fuel for Power Station. Summary Report on Tests with Monkeys, Rats and Mice.
Author:
New Energy Development Organization
Year:
1987
Bibliographic source:
New Energy Development Organization, Tokyo
Reference Type:
publication
Title:
Long-term effects of methanol vapor at low concentration.
Author:
Takeda, K. and Katoh, N.
Year:
1988
Bibliographic source:
Proc. of the 8th Int. Symp. Alcohol Fuels, 1051-1056, Tokyo, Japan

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Not all parameters mentioned in the guideline were investigated, limited documentation
Principles of method if other than guideline:
According to national standards. Comprehensive study programme on three species (rat, mouse, monkey) including metabolic, pharmacokinetic, short-, long-term, reproduction and carcinogenicity studies.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Methanol
EC Number:
200-659-6
EC Name:
Methanol
Cas Number:
67-56-1
Molecular formula:
CH4O
IUPAC Name:
Methyl alcohol

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing: individually

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: H 1000 multi-tiered inhalation chambers, Hazleton Systems Inc., USA (volume 2.5 m³)
- Method of holding animals in test chamber: pregnant females were individually housed in wire mash stainless steel cages with 24 rooms placed in the inhalation chamber (whole body exposure)
- Source and rate of air: filtered external air, ventilation rate of 30 (not further specified)
- Method of conditioning air: passed through a medium performance filter, a high performance filter and an activated carbon filter
- System of generating vapours: total vaporizer supplied with liquid methanol by a microprecision pump, vaporization into the filtered air
- Temperature, humidity, pressure in air chamber: 23-26°C, 50-65%, atmospheric pressure
- Air flow rate: 1250 L/min
- Air change rate: 30/h
- Method of particle size determination: not applicable
- Treatment of exhaust air: not specified

TEST ATMOSPHERE
- Brief description of analytical method used: air from the inhalation chamber was extracted at a rate of 1.0 L/min by a sampling apparatus and the methanol concentration measured by a methanol vapor analyzer incorporating an infra-red spectrophotometer. The concentration signal was transmitted to the microprecision pump and used to regulate the methanol concentration in the chamber by adjusting liquid flow.
- Samples taken from breathing zone: no
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.
Details on mating procedure:
- Impregnation procedure: pregnant females, not further specified
Duration of treatment / exposure:
GD 7-17
Frequency of treatment:
continuously, approx. 22.7 h/d
Duration of test:
various durations: until Cesarian section, the age of 8 weeks, and reproduction of F1, respectively
Doses / concentrationsopen allclose all
Dose / conc.:
270 mg/m³ air
Dose / conc.:
1 330 mg/m³ air
Dose / conc.:
6 650 mg/m³ air
No. of animals per sex per dose:
36 dams per test and control group, including 12 dams allowed for natural delivery.
Control animals:
yes, concurrent no treatment

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION: Yes
WATER CONSUMPTION: Yes
POST-MORTEM EXAMINATIONS: Yes
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Other: embryolethality
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
mortality observed, treatment-related
Description (incidence):
One dam died, another one had to be killed before delivery.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
a decrease in body-weight gain at 5000 ppm
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption was reduced during gd 7 through 12 at 5000ppm
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Drinking water consumption was reduced during gd 7 through 12 at 5000ppm
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
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:
no effects observed
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
late resorptions: 10.4 % vs. 0.6 % in control, p<0.05 at 5000 ppm, ), but the variance between single litters was high
Dead fetuses:
no effects observed
Changes in pregnancy duration:
effects observed, treatment-related
Description (incidence and severity):
After 5000 ppm, mean gestation time was prolonged by 0.7 days.
Changes in number of pregnant:
not examined

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
1.33 mg/L air
Basis for effect level:
maternal abnormalities
Key result
Dose descriptor:
LOAEC
Effect level:
6.65 mg/L air
Basis for effect level:
maternal abnormalities
mortality
other: body weight gain, food and drinking water consumption

Maternal abnormalities

Key result
Abnormalities:
effects observed, treatment-related

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weight of live fetuses after Cesarian section was reduced (about -20 %, p<0.001) at 5000 ppm
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
Among descendants from the high-dose group, mortality was prominent during the first 4 d after birth with live fetuses showing poor vitality in this time (ca. 10% = 2/12 pups per litter died as compared with 1 to 2% fatal cases in the other groups).
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Only after intra-uterine exposure to 5000 ppm: "atresia of cervical arch/vertebra foramen costotransversarium" (45 %), " bifurcated vertebral center" (14 %) and "cervical rib" (65 %) as well as "excessive sublingual neuropore" (50 %), all of which malformations having no or little relevance in the other group except of "atresia foramen" with about 25 % in the control and about 4 to 8 % in the other exposure groups
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
Only after intra-uterine exposure to 5000 ppm: About 50 % of the fetuses with ventricular septal defects (visceral malformation in 16/20 litters or 64/131 fetuses) vs. 0% or near 0% in all other groups, and residual thymus (variation in all 20 litter or 70/131 fetuses) vs. about 2.4 to 2.9 % in 4 litters each of all other groups.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
After 5000 ppm, food and drinking water consumption of dams was reduced also after birth during lactation. Slight retardation of growth was still significant at weaning. Water consumption was slightly reduced, in particular for females.
Early indicators for post-natal development:
In pups from the 5000-ppm group, eruption of upper incisor and opening of eyelid for both sexes and descensus testis for males were significantly earlier than in the controls in relation to term of delivery, but not in relation to the whole gestation time which was prolonged for this group. There were no differences in behavioral and functional tests as compared to control and other test groups. At the age of 8 weeks, brain, thyroid (males), thymus and testis (males) weights were lower (p<0.01), and pituitary-gland weight of males was higher (p<0.05). But histological examination revealed no treatment-related changes. 16.5 % of the offsprings (15/91 in 8/12 litters) had hemilateral thyroprivia (missing thyroid lobe, mostly left). There was no histopathological lesion in the tissue. The defect was attributed to an impairment of organogenesis.
Reproductive performances of F1 (from 5000 ppm):
No significant effects on sexual cycle, genital function and reproductive performance of the F1 progeny were noted.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
1.33 mg/L air
Basis for effect level:
other: teratogenicity
Key result
Dose descriptor:
LOAEC
Effect level:
6.65 mg/L air
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: visceral and skeletal malformations, postnatal growth and survival

Overall developmental toxicity

Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
6.65 mg/m³ air
Treatment related:
yes

Any other information on results incl. tables

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 exposure to 5000 ppm of pregnant rats during gestation (>20 h/d) produces maternal toxicity, fetal malformation, increased perinatal mortality and developmental delay in surviving progeny. Teratogenic effects occurred only at maternally toxic exposure concentration. Exposure levels of 1000 ppm or less did not induce toxic symptoms in maternal animals, structural abnormalities or delay in growth or functional development in the F1-generation. Therefore, the NOEC for maternal and developmental toxicity is considered to be 1000 ppm.