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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose 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: see 'Remark'
Remarks:
GLP guideline study. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.

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

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:
- 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)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 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: the test substance was delivered to heated evaporators by mean of metering pumps. The warmed air was mixed with compressed air and delivered to teh 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 (ciontrol 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
Read-across justifications and data matrices are presented in IUCLID section 13.


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

CLINICAL SIGNS AND MORTALITY


BODY WEIGHT AND WEIGHT GAIN


FOOD CONSUMPTION


FOOD EFFICIENCY


WATER CONSUMPTION


OPHTHALMOSCOPIC EXAMINATION


HAEMATOLOGY


CLINICAL CHEMISTRY


URINALYSIS


NEUROBEHAVIOUR


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

    Read-across justifications and data matrices are presented in IUCLID section 13.
    
    
    

Read-across justifications and data matrices are presented in IUCLID section 13.

Read-across justifications and data matrices are presented in IUCLID section 13.

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. T

The concentration of 120 ppm corresponds to the calculated

saturated vapor concentration at 20°C.

Applicant's summary and conclusion

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 (120 ppm is equivalent to saturation at 20°C). 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).