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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
no
GLP compliance:
yes
Remarks:
(CIVO TNO)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Methyl vinyl ether, obtained from BASF AG;
purity 99.7%
impurities: ethylvinylether 0.25%, methanol < 0 .1% , and water 0.05%
The stability of the test material was confirmed by reanalysis

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
breeder: Winkelmann, Versuchstierzucht GmbH & Co. KG, Borchen, Germany)
Mean body weights: 140 g and 121 g for males and females, respectively, at start of the study.
Feeding: the Institute's standard diet ad libitum, not during exposure
Drinking water: tap water ad libitum, not during exposure
acclimatisation: 10 days
no further data

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: air
Remarks on MMAD:
MMAD / GSD: not applicable
Details on inhalation exposure:
Whole-body exposure in glass cylinders (length 0.90 m, diameter 15 cm). Temperature during exposure: 21 °C. Relative humidity during exposure: 43 - 51%. Test atmosphere generation: mixing an adjustable flow of methyl vinyl ether vapour with the main air flow to the glass cylinders.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Exposure levels: analyses of the test atmospheres were performed by infra-red spectroscopy at least four times per hour. See Table below.
Duration of treatment / exposure:
28 days
Frequency of treatment:
6 hrs/day, 5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 500, 3500, 25000 ppm (0, 1.2, 8.4, or 60 mg/L)
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 500, 3480, 25080 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
Positive control:
no

Examinations

Observations and examinations performed and frequency:
clinical signs: twice a day (once before the start of the exposure and once after the exposure); during the weekends once a day.
Body weights: recorded just prior to the start of the study and then weekly.
Haematology: red and white blood cells, haemoglobin, diff. white blood cell counts, haematocrit, prothrombin time, reticulocyte counts, MCV, MCH, MCHC. Blood samling: tip of the tail at the end of the exposure period.
Clinical chemistry: albumin, GOT (or ASAT), alkaline phosphatase, GPT (or ALAT), gamma-GT, urea, total protein, creatinine, total bilirubin, Ca, K, Na, inorganic phosphate, Cl, glucose; blood samples of abdominal aorta at autopsy.
Sacrifice and pathology:
Pathology
Animals killed at day 28, autopsied and examined for gross pathological changes.
Organ weights of adrenals, brain, heart, kidneys, liver, lungs with mediastinal lymph nodes, trachea and larynx, spleen, testes measured
Histopathological examination was done on all organs and tissues collected of all rats (adrenals, brain, heart, kidneys, liver, lungs with mediastinal lymph nodes, trachea and larynx, spleen, testes, sternum, nose).
Other examinations:
no
Statistics:
Statistical data analysis included analysis of co-variance followed by the Dunnett test (body weights), Fischer Exact test (incidences of histopathological changes), and analysis of variance and Dunnett test (organ weights, hematological and biochemical data).
Level of significance: p<=0.05

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
Mortalities: none in either group.
Animals exposed to 25000 ppm showed transient restlessness and pilo-erection.
Body weights: Statistically significantly (p <= 0.05) reduced body weights in high-dose males throughout the study. Reduced weight in mid-dose males and high-dose females gaining statistical significance at week 1 (males) and week 3 (females).

Hematology (all data means +-SEM): The number of white blood cells was reduced in males, significantly at 500 and 3500 ppm (16.5+-1.5, 11.4+-0.6, 12.2+-1.1, 13.1+-0.8, respectively); the effect was not dose-related. Prothrombin times were increased (not significant) compared to controls in all exposed males and in high-dose females.
Blood chemistry: Total protein was decreased in all male dose groups (p <= 0.01; 56.7+-0.5, 53.8+-0.3, 53.4+-0.2, 52.8+-0.8 g/L, respectively); GOT was decreased in the high-dose group (p < 0.01; 51.1+-0.7 versus 60.3+-2.0 U/L in control).

Organ weights: absolute, but not relative, spleen and lung weights were decreased (p <= 0.05) in male groups at the intermediate and the high-dose-level. Relative liver weight of the high-dose female group was significantly (p <0.05) increased. It tended to be higher in females than in males. Testes weights unaffected at all dose levels.
Gross pathology: no treatment-related findings noted.
Histopathology: decrease of the number of olfactory epithelial cells in high-dose groups. The effect was more pronounced in females than in males. No incidence of reduced spermatogenesis, interstitial edema, or multinucleated giant-cells in any treatment group; incidence in control group animals 1/5 each.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
3 500 ppm
Sex:
female
Basis for effect level:
other: (8.4 mg/L)
Dose descriptor:
LOAEC
Effect level:
25 000 ppm
Sex:
female
Basis for effect level:
other: reduced body weight, clinical signs and local effects (atrophy of olfactory epithelium)
Dose descriptor:
LOAEC
Effect level:
500 ppm
Sex:
male
Basis for effect level:
other: (1.2 mg/L); lowest dose tested; increased prothrombin time, decrease in total protein

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No data available on historical control data for haematology and clinical chemistry of this lab and this strain.

Applicant's summary and conclusion

Conclusions:
The NOAEC was 3500 ppm for females, local effects on the olfactory epithelium, clinical signs and reduced body weight were detected at 25000 ppm.
No NOAEC could be established for males because of the
increased prothrombin time and the decreases in total
protein in all male dose groups.
Executive summary:

GLP guideline study.

A 4 -week inhalation toxicity study in rats was carried out with methyl-vinyl ether. Four groups of 5 male and 5 female Wistar rats each, were exposed (whole body) to target concentrations of 0, 500, 3500, 25000 ppm (0, 1.2, 8.4, or 60 mg/L) for 6 hours a day, five days a week during a period of four weeks. Clinical signs, body weights, weekly food consumption, haematological and biochemical parameters, gross- and microscopic pathology were used to examine the toxicological potency of the test substance. No NOAEC was identified for male rats; increased prothrombin time and decrease in total protein was found in all treatment groups. Therefore a 2nd study in male rats was performed (see next study record). The NOAEC for females was 3500 ppm; at 25000 ppm local effects on the olfactory epithelium, clinical signs and reduced body weight were found.

Conclusion: The NOAEC was 3500 ppm for females, local effects on the olfactory epithelium, clinical signs and reduced body weight were detected at 25000 ppm. No NOAEC could be established for males because of the increased prothrombin time and the decreases in total protein in all male dose groups.