Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
no data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Peer-reviewed publication with summarized results. The study was GLP complient and performed according to OECD guideline 413.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1998

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
purity grade: 99.9%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: SPF-Wistar, Chbb: THOM
- Source: Dr. K. Thomae GmbH, D-88400 Biberach/Riss, Germany
- Age: 7 weeks
- Weight at study initiation: mean body weight male: 238 g; female: 170 g
- Housing: individually in wire cages in the inhalation chamber
- Diet (ad libitum): KLIBA rat/mouse laboratory diet 24-343-4 (Klingentalmühle, AG, CH-4303 Kaiseraugust, CH)
- Water (ad libitum): tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
The different 2-Ethylhexanol (2-EH) inhalation chamber concentrations were achieved by conveying the substance via continuously operating metering pumps to evaporators. For 15, 40 and 120 ppm 2-EH the vapour generation was carried out in a thermostated glass container (maintained at 46.4- 50.4°C) with a downstream mixing unit. 40 and 120 ppm atmospheres were generated by means of a two-component atomizer using compressed air and evaporation of the 2-EH-aerosol. The warmed air of the control group (45.7°C) and the vapour-air mixture of the 2-EH groups were then mixed with the overall stream and distributed to a horizontal-flow whole-body exposure system (inhalation chamber glass/steel construction with volumes of approx. 1.1 m³ manufactured by BASF AG, Ludwigshafen, Germany). In the inhalation chamber of the control group, the exhaust air system was set lower (positive pressure), in the 2-EH inhalation chambers the exhaust air system was set higher than the supply air system (negative pressure). Pressure (mean chamber pressure from - 10.2 to 10.1 Pascal) and temperature (mean temperature 23.1°C to 23.8°C) were measured continuously. The relative humidity (mean relative humidity 41.8% to 46.2%) was checked and recorded once daily.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the inhalation atmospheres were analyzed at intervals of about 15 min by gas chromatography (Hewlett Packard gas chromatograph Model HP 5880 A with automatic sampler HP 7671 A, FID, column: 1 m x 2 mm with 10% Triton x 305 on Supelcoport, 102/ 120 rnesh, oven temperature: 120°C. C15-paraffin was used as internal standard).
Duration of treatment / exposure:
6 h on workdays over a period of 90 days (65 exposures)
Frequency of treatment:
5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
120 ppm
Basis:

Remarks:
Doses / Concentrations:
40 ppm
Basis:

Remarks:
Doses / Concentrations:
15 ppm
Basis:

No. of animals per sex per dose:
10 m/10 f per group
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
Individual body weights: beginning of the preflow period, 1 day before commencement of the exposure period and weekly throughout the study.
Body weight gain: The difference between the body weight on the day of weighing and that of the preceding weighing was calculated as group mean average.
Clinical signs and mortality: daily
Ophthalmological examinations: prior to the beginning of the preflow period and at the termination of the study using an ophthalmoscope.
Blood for clinical pathology testing was collected in randomized order by retro-orbital bleeding.
Haematology: white blood cells, red blood cells, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets, differential blood count – on day 94 of the study
Clinical chemistry: sodium, potassium, chloride, inorganic phosphate, calcium, urea , creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase - on day 94 of the study
Sacrifice and pathology:
At the end of the 90-day exposure period all animals were necropsied and assessed by gross pathology. The body weight and the weight of the lungs, liver, kidneys, adrenal glands and testes were determined. Organs or tissues required by guidelines to be tested as well as all gross lesions were fixed in a 4% formaldehyde solution.
Histological examination and assessment of findings were carried out after histotechnical processing and staining with haematoxylin and eosin.
Statistics:
Mean values and standard deviation were calculated for body weight and body weight change, haematological and clinical biochemistry parameters as well as for absolute and relative organ weights. The organ weights were statistically evaluated using the Dunnett's test (Dunnett 1955 and 1964) for comparison of the exposure groups with the control group. The analysis of variance (Cochran, 1957) with subsequent Dunnett's test (Dunnett 1955 and 1964) was used to compare body weight, body weight change as well as haematological and clinical biochemistry data of the treatment groups with those of the control group.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
not dose-related and therefore of no toxicological relevance
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Details on results:
Analysis of the daily inhalation chamber concentrations revealed that the values obtained closely fitted with the desired nominal level.
There were no effects regarding clinical signs; mortality; body weight gain; ophthalmoscopic examination; haematology; clinical chemistry; organ weights; histopathology at any dose level.
Under the conditions of the test no treatment-related toxic effects were found in male and female Wistar rats which were exposed to 2-ethylhexanol vapor up to 120 ppm, corresponding to 638.4 mg/m³. The concentration of 120 ppm corresponds to the calculated saturated vapor concentration at 20°C.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
120 ppm (analytical)
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight gain; ophthalmoscopic examination; haematology; clinical chemistry; organ weights; histopathology
Dose descriptor:
NOAEL
Effect level:
638.4 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight gain; ophthalmoscopic examination; haematology; clinical chemistry; organ weights; histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on these results, for male and female Wistar rats the NOAEL of inhaled EH was 120 ppm corresponding to 638.4 mg/m³.
Executive summary:

A 90-day subchronic inhalation toxicity study was performed on Wistar rats in accordance to OECD testing guidelines to evaluate the toxicological profile of 2-ethylhexanol, potential target organs, and a no-observable-adverse-effect-level (NOAEL). 10 males and 10 females per group were exposed to 2-ethylhexanol vapours at concentrations of 15, 40 and 120 ppm (the latter corresponding to the vapour saturation at 20°C) 6 hours/day for 90 days. The respective controls inhaled clean air under the same conditions. No substance-related adverse effects were observed for body weight, body weight gain, mortality, organ weights, clinical biochemistry and haematological parameters including clotting time. There were no findings related to the treatment with 2 -ethylhexanol either at necropsy or at histological examination. The highest concentration tested under these conditions (120 ppm corresponding to 638.4 mg/m³) was found to be the NOAEL for male and female rats.