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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedures in accordance with accepted standard methods, limited documentation.
Cross-reference
Reason / purpose:
reference to same study

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:
Methanol, Environmental Health Criteria 196
Author:
IPCS/WHO
Year:
1997
Bibliographic source:
International Programme on Chemical Safety, World Health Organisation Geneva, 1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
- limited documentation
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): methanol (reagent special grade from Junsei Chemicals Co.)
- Physical state: vapour
- Analytical purity: no data
- Impurities (identity and concentrations): < 1 ppm vinyl chloride, < 3 ppm formaldehyde

Test animals

Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Inc.
- Housing: The animals were housed individually in wire-mash cages attached to the inhalation chamber.
- Diet (e.g. ad libitum): solid chow for rats (CRF-1, Charles River Japan Inc.)
- Water (e.g. ad libitum): filtered and sterilised tap water
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 55 ± 15 %
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Remarks on MMAD:
MMAD / GSD: not applicable
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hazleton 1000 Inhalation Exposure Chamber
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical control of chamber concentration: analytical values close to nominal ones.
Duration of treatment / exposure:
12 months (total exposure time: 7318-7341 h: males; 7474 - 7496 h: females)
Frequency of treatment:
continuously, average about 20 h/d
Doses / concentrations
Remarks:
Doses / Concentrations:
0.013; 0.13; 1.3 mg/L (corresponding to 10; 100; 1000 ppm)
Basis:
nominal conc.
No. of animals per sex per dose:
20
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes


DETAILED CLINICAL OBSERVATIONS: Yes


BODY WEIGHT: Yes


FOOD CONSUMPTION:
- The feed to be consumed during a week was determined for two animals, and the daily food consumption per animal was then calculated. The calculation was done weekly during the first 13 weeks of exposure, and monthly thereafter.


HAEMATOLOGY: Yes


CLINICAL CHEMISTRY: Yes


URINALYSIS: Yes


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
All the data obtained were analysed by t-test, Fischer´s exact test or Armitage´s chi-square test as appropriate for any significant difference.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
One female rat of the 1.3 mg/L dose group and one male rat of the 0.013 mg/L dose group died or were sacrificed in extremis (on day 337 and on day 340, respectively). This was considered spontaneous on the basis of the absence of a consistent dose relationship.


BODY WEIGHT GAIN AND FOOD CONSUMPTION
A very slight transient suppression of body-weight gain was observed for males and females of the 1.3 mg/L dose group from week 27 through 44 (less than 5 %). This has to be attributed to temporary occurrence of slight diarrhea in these groups during this period. The otherwise addressed significant decreases in body weight at the end of the study are not noticable in Fig. 3 representing the time-course of body weight development. The high-dose males showed a minimal, but significant decrease in food consumption from week 30 to the end. However, this was not more than about 5- % of the control.


HAEMATOLOGY
Hematologic examinations revealed no clear changes which could be attributed to exposure to methanol.


CLINICAL CHEMISTRY
Serum biochemical examination showed a small tendency to decrease for alkaline phosphatase, the enzymatic activities of GOT, GPT, LDH and gamma-GTP did not show any differences.
Free fatty acid showed lower values in all exposure groups without dose-response relationship. Cholesterol and triglyceride remained unchanged.
Changes of other clinical-chemical parameters showed no correlation with the methanol exposure.


URINALYSIS
Urinalysis showed no changes suggesting effects from exposure to methanol.


ORGAN WEIGHTS
Data of the organ/body weight ratio revealed a dose-related upward tendency in the liver and spleen for females which remained within a 5-% range.


GROSS PATHOLOGY
no data


HISTOPATHOLOGY:
Histopathological examinations showed a variety of non-tumoral changes in various organs, many of them were infrequent findings which were possibly accidental. For tumoral changes, similarly, almost all the findings observed were considered spontaneous ones due to aging.

Except for swelling of chromophobic cells of the pituitary, there was no findings which could be related to exposure level.


Effect levels

open allclose all
Dose descriptor:
NOEC
Effect level:
0.13 mg/L air (nominal)
Sex:
male/female
Dose descriptor:
LOAEC
Effect level:
1.3 mg/L air (nominal)
Sex:
male/female
Basis for effect level:
other: body weight and food consumption; organ/body weight ratio; swelling of the chromophobic cells of the pituitary

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

According to the authors, only in the 1.3 mg/L dose-group changes could be considered treatment-related. But based on the minor degree and severity, these changes have no pathological meaning and may be considered as toxicologically irrelevant.

Levels of 0.13 mg/L or less (at 20 h/d) did not produce any effect (= NOEC). 1.3 mg/L is adopted as LOAEC, although it may

be considered as a NOAEC.

Applicant's summary and conclusion