Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
ca. 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
No data on batch no. Limited reported study. Focus on absorption, distribution and elimination. OECD guideline 417 was not in place yet. This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report Date:
1978

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
The present study in rats was meant to evaluate (a) absorption, (b) distribution pattern in various organs and tissues, and (c) elimination rate from these tissues and organs. The applicable OECD test guideline 417 was not in place yet.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: 99.8-99.9%
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: no info
- Weight at study initiation: 280-300 g
- Fasting period before study: not applicable
- Housing: no info
- Individual metabolism cages: no (not applicable in this case)
- Diet (e.g. ad libitum): ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: 8-14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no info
- Humidity (%): no info
- Air changes (per hr): no info
- Photoperiod (hrs dark / hrs light): no info

Administration / exposure

Route of administration:
other: gaseous exposure via intratracheal canula (under narcosis)
Vehicle:
other: air
Details on exposure:
TYPE OF INHALATION EXPOSURE: via tracheal canula

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: via tracheal canula
- Method of holding animals in test chamber: a system was used consisting of 2 mixing chambers and 1 'breathing chamber' from which the animal breathed the test atmosphere via the trachea canula; animal under narcosis
- Source and rate of air: Test substance was mixed with main air supply
- Method of conditioning air: no info
- System of generating gas: mixed via spray can with nozzle with main air supply
- Composition of vehicle (if applicable): air
- Concentration of test material in vehicle (if applicable): between 700 and 2000 ppm
- Method of particle size determination: not applicabe (gas)
- Treatment of exhaust air: not indicated

TEST ATMOSPHERE (if not tabulated)
- Concentration: the DME concentrations in the 'breathing chamber' were measured with GC-MS analysis (GC headspace using an exact amount of diethylether as reference compound. In preliminary tests it was shown that equilibrium between organ/tissue, water and air was reached within 6 h and that no changes occurred within the next 18 h.
- Particle size distribution: not applicable (gas)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): not applicable (gas)
Duration and frequency of treatment / exposure:
30 or 60 min
Doses / concentrations
Remarks:
Doses / Concentrations:
1000 ppm (60 min) - first test
745, 1000, 1280, 1790 and 1960 ppm (30 min) - second test
No. of animals per sex per dose:
2-3 males per concentration per sacrifice point
Control animals:
yes, sham-exposed
Positive control:
No
Details on study design:
- Dose selection rationale: no info
- Rationale for animal assignment (if not random): no info
Details on dosing and sampling:
First study:
PHARMACOKINETIC STUDY (Absorption, distribution, elimination)
- 1000 ppm, 60-min exposure, 3 animals per time point
- Tissues and organs sampled: blood, heart, lungs, liver, spleen, kidneys, fat, muscles, brain
- Time and frequency of sampling: during exposure at 5, 10, 30 and 60 min; and 15, 45 and 90 min after exposure

Second study:
PHARMACOKINETIC STUDY (Absorption, distribution)
- between 700 and 2000 ppm, 30-min exposure, 2 animals per concentration
- Tissues and organs sampled: blood, heart, lungs, liver, spleen, kidneys, fat, muscles, brain
- Time and frequency of sampling: at the end of the 30-min exposure period (therefore no elimination measured)
Statistics:
Not used.

Results and discussion

Preliminary studies:
Not done

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Study #1: DME was measured in all organs/tissues examined, therefore it was absorbed. The ratio of DME in test atmosphere and blood was 65:1, at a concentration of 1000 ppm.
Study #2: DME was measured in all organs/tissues examined, therefore it was absorbed.
Details on distribution in tissues:
Study #1: In the beginning, DME concentration in muscles and fat is lower than in the other tissues/organs. In the other tissues/organs, the concentrations were comparable to that in blood. Later, the concentration of DME in fat increased and finally was about 30% higher than in blood and the other organs. At about 30 min, a steady state level was obtained.
Study #2: The test substance concentrations in all organs/tissues examined at 'steady-state' are linearly proportional to the DME concentration in air (in the range of 750-2000 ppm)
Transfer into organs
Test no.:
#1
Transfer type:
blood/brain barrier
Observation:
other: same level in brain as in other organs/tissues (except fat)
Details on excretion:
Study #1: After the 60-min exposure duration, the concentrations of DME decreased rapidly in all organs/tissues. The elimination constant in the alpha-phase is about 10-15 min, the elimination constant in the beta-phase is higher, ca. 90 min (slower elimination). The test substance concentration in muscles and fat decreases at a slower rate than that in the other organs/tissues.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: ca. 2.7 - 3.4 h (depending on organ/tissue)
Test no.:
#1
Toxicokinetic parameters:
AUC: ca. 10 - 15 ppm (depending on organ/tissue)
Test no.:
#1
Toxicokinetic parameters:
Cmax: ca. 22 - 29 ppm (depending on organ/tissues)

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Not measured

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: low bioaccumulation potential at 1000 ppm
1. Following exposure to 1000 ppm DME, the increases in DME concentration in various organs/tissues, including brain, were rapid and similar except for a slower increase in fat and muscles.
2. At ca. 30 min exposure to 1000 ppm, steady state levels were reached; levels were similar in all organs/tissues except for fat in which ca. 30% higher levels were obtained.
3. After 1-h exposure to 1000 ppm, DME levels decreased rapidly and equally, although a little slower in fat.
4. The DME levels in organs/tissues at steady state level (30-min exposure) were linearly proportional to the DME concentration in air in the range of 750 to 2000 ppm.
Executive summary:

The study was performed to investigate the toxicokinetics of the test material, DME, following a single 1 -h inhalation exposure to male Wistar rats. The study was not performed according to OECD 417 as this guideline was not in place yet. Group of 3 male animals were exposed to 1000 ppm (1.9 mg/L) via a tracheal canula. The animals were necropsied after 5, 10, 30 or 60 min after the start of exposure, or 15, 45 or 90 min after exposure. DME concentrations were determined in blood, heart, lungs, liver, spleen, kidneys, fat, muscles and brain. Following exposure to 1000 ppm DME, the increases in DME concentration in these organs/tissues, including brain, were rapid and similar except for a slower increase in fat and muscles. At ca. 30 min exposure to 1000 ppm, steady state levels were reached; levels were similar in all organs/tissues except for fat in which ca. 30% higher levels were obtained. After 1 -h exposure to 1000 ppm, DME levels decreased rapidly and equally, although a little slower in fat. It was, therefore, concluded that DME has a low bioaccumulation potential at 1000 ppm.

Other groups were exposed also via tracheal canula to concentrations between 745 and 2000 ppm (between 1.4 and 3.8 mg/L) DME for 30 min. The animals were necropsied immediately after exposure. DME concentrations were again determined in blood, heart, lungs, liver, spleen, kidneys, fat, muscles and brain. The DME levels in organs/tissues at steady state level (30 -min exposure based on the first study) were linearly proportional to the DME concentration in air in the range of 750 to 2000 ppm.

The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).