Registration Dossier

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

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1998
Report Date:
1988
Title:
No information
Author:
EPA
Year:
1992
Bibliographic source:
Document No. 86-920001004, Microfiche No. OTS0536862
Report Date:
1992
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

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:
- Name of test material (as cited in study report): 2-Ethylhexanol (EH)
- Analytical purity: 99.9%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at delivery: 7 weeks
- Weight at study initiation: males 238 (+/- 2.3) g; females 238 (170 +/- 2.2) g
- Housing: singly in wire cages
- Diet: e.g. ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days acclimation to the inhalation chamber


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


IN-LIFE DATES: From: day1 To: day 93

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: vapour exposure, therefore MMDA not relevant
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: horizontal-flow whole-body inhalation chamber (glas/steel construction, volumes approx. 1.1 m³)
- Method of holding animals in test chamber: rats were kept individually in wire cages
- Test atmosphere generation: For test groups the test substance was delivered to heated evaporators (maintained at 46.4-50.4 °C) by mean of metering pumps. The 40 and 120 ppm test atmosphere was generated using an additional two-component atomizer. In all cases the warmed air was mixed with compressed air (overall stream) and delivered to the inhalation chamber.
- Source and rate of air: compressed air; variable rate
- Temperature, humidity, pressure in air chamber: 23.1 to 23.8°C; positive pressure 10.1 Pascal (control groups), negative pressure -10.2 Pascal (treated groups); 41.8 to 46.2% relative humidity
- Air flow rate: not reported in publication
- Air change rate: not reported in publication
- Treatment of exhaust air: not reported in publication

TEST ATMOSPHERE
- Brief description of analytical method used: samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day, 5 days/week (total of 65 exposures)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 15, 40 and 120 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
15 (SD 0.67), 39.9 (SD 1.33), 120 (SD 4.8) ppm
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: none
Positive control:
not required

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS:
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: yes
- Time schedule: pre-treatment and at termination

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption: no data contained in the publication; not required

FOOD EFFICIENCY:
- Body weight gain: yes, but no data contained in the publication; not required

WATER CONSUMPTION: no data contained in the publication; not required

OPHTHALMOSCOPIC EXAMINATION: yes
- Time schedule for examinations: pre-treatment and at termination
- Dose groups that were examined: all animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination, day 94 of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals
- Parameters: white and red blood cells, hemoglobin, hematocrit, mean corpuscular volume. mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, differential blood count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination, day 94 of the study
- Animals fasted: No data
- How many animals: No data
- Parameters: sodium, potassium, chloride, glucose, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, clotting time

URINALYSIS: No data

OTHER:
- cyanide-insensitive palmitoyl-CoA oxidation in liver homogenates
- gross pathology of all animals at termination; determination of organ weights (lungs, liver, kidneys, adrenal glands, and testes)
- histopathology of organs/tissues required by guidelines, and all gross lesions
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
- Mean values +/- standard deviation: body weight, body weight gain, hematological and clinical biochemistry parameters, absolute and relative organ weights.
Dunnett's test: comparison of exposure groups with the control group.
Analysis of variance subsequent to Dunnett's test: body weight, body weight gain, hematological and clinical biochemistry parameters

Results and discussion

Results of examinations

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
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
1) Analysis of the daily inhalation chamber concentrations revealed that the values obtained closely fitted with the desired nominal level

2) There were no effects regarding the issues below noted at any dose level:

CLINICAL SIGNS AND MORTALITY

BODY WEIGHT AND WEIGHT GAIN

OPHTHALMOSCOPIC EXAMINATION

HAEMATOLOGY

CLINICAL CHEMISTRY

ORGAN WEIGHTS

GROSS PATHOLOGY

HISTOPATHOLOGY: NON-NEOPLASTIC

HISTOPATHOLOGY: NEOPLASTIC (if applicable)


Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
120 ppm (analytical)
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
NOAEC
Effect level:
638.4 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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 vapour up to 120 ppm. According to the study authors the concentration of 120 ppm (638.4 mg/m3) corresponds to the calculated saturated vapour concentration at 20°C. However using the highly reliable and newly available vapour pressure of 0.93 hPa a saturation vapour concentration of up to 4884 mg/m³ can be calculated. Concerning the fact that this study did not include test concentrations up to saturation concentration and no toxic effect was observed, the systemic inhalation hazard arising from exposure to 2 -EH might be overestimated when using the NOAEC of 120 ppm.

Applicant's summary and conclusion

Conclusions:
No adverse effects were seen in this 90 day inhalation toxicity study (OECD TG 413) in male and female WIstar rats tested up to concentrations of 120 ppm (which was equivalent to saturation at 20°C according to the study authors). Thus the NOAEC of this study was 120 ppm, i.e. 638.4 mg/cubicmetre.
Executive summary:

No treatment-related effects were noted in a OECD Guideline 413 study (Subchronic Inhalation Toxicity: 90-Day) conducted under GLP conditions and using male and female Wistar rats (10 rats per sex and dose). Exposure levels were 0, 15, 40, and 120 ppm. As there were no effects compared with the control groups in either sex on body weight or body weight gain, clinical signs of toxicity and mortality, hematological and clinical biochemistry parameters, ophthalmological parameters, absolute or relative organ weights including testes, or cyanide-insensitive palmitoyl-CoA oxidation as a parameter for hepatic peroxisome proliferation, the NOAEC was 120 ppm, ie. 638.4 mg/m³ (Klimisch, 1998).