Bis(2-chloroethyl) ether

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Evidence of chloroethylene oxide being the reactive metabolite of vinyl chloride towards DNA: comparative studies with 2,2' -dichlorodiethylether

Author:

Gwinner, L.M., Laib, R.J., Filser, J.G., Bolt, H.M.

Year:

1983

Bibliographic source:

Carcinogenesis, 11:1483-1486

Materials and methods

Objective of study:

distribution

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Inhalation exposure to radiolabelled DCEE in a closed all-glass exposure system
- Short description of test conditions: A single dose corresponding to 0.25 mCi/animal (final uptake) was given to three rats. The rats were sacrificed after 24h.
- Parameters analysed / observed: distribution in organs

GLP compliance:

no

Remarks:

pre-GLP

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-chloroethyl) ether

EC Number:

203-870-1

EC Name:

Bis(2-chloroethyl) ether

Cas Number:

111-44-4

Molecular formula:

C4H8Cl2O

IUPAC Name:

1-chloro-2-(2-chloroethoxy)ethane

Test material form:

liquid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Name (as cited): 2,2'-Dichlorodiethylether (BCEE)
- Purity: 99%
- Source of test material: Merck-Schuchard

RADIOLABELLED TEST MATERIAL
- Name (as cited): [1-14C]2,2'-Dichlorodiethylether
- Radiochemical purity: no specified
- Source of test material: NEN Chemicals
- Specific activity: 1.42 mCi/mmol

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ivanovas, Kissleg, FRG
- Age at study initiation: not specified
- Weight at study initiation: 200g
- Diet: ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

At the start of the experiment the glass chamber, where the three rats were housed, was filled with vapor of radiolabelled BCEE. After 18 h exposure > 95% of the administered BCEE was taken up by the animals. Uptake was 0.25 mCi/animal.

Doses / concentrations

Dose / conc.:

125.9 mg/kg bw (total dose)

Remarks:

Calculated based on the specific activity of radiolabelled BCEE (1.42 mCi/mmol), the uptake of test animals (0.25 mCi/animal) and the animal weight (200 g).

No. of animals per sex per dose / concentration:

3 animals

Control animals:

no

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY
- Test chamber: closed all-glass exposure system
- Dose: 0.25 mCi/animal
- Time of sampling: 24 h post-exposure
- Tissues sampled: Liver, kidney, spleen, lung, small intestine and muscle tissues
- Sample storage: - 80°C
- Parameter measured: irreversible binding of radioactive metabolites of [1-14C]BCEE to tissue proteins
- Other: The decline of BCEE vapor in the inhalation chamber was measured by gas chromatography. After 18 h exposure >95% of the administered BCEE was taken up by the animals.

Results and discussion

Main ADME results

Type:

distribution

Results:

Irreversibly protein bound radiolabelled BCEE was mainly found in the liver. Smaller amounts were found in kidney, small intetsine, lung and spleen.

Any other information on results incl. tables

The relative distribution of irreversible protein binding in different rat tissues after exposure of the animals to [¹⁴C]BCEE as observed in this study is presented in the table below:

Tissue	% of radioactivity irreversibly bound per g tissue protein (n = 4)
Liver	0.32 +/- 0.016
Lung	0.07 +/- 0.015
Spleen	0.06 +/- 0.014
Kidney	0.17 +/- 0.024
Small intestine	0.12 +/- 0.017
Muscle	0.01 +/- 0.003

Applicant's summary and conclusion

Conclusions:

3 male rats were exposed to radiolabelled BCCE by inhalation (dose: approc. 125.9 mg/kg BCEE). After 18 h exposure > 95% of the administered BCEE was taken up by the animals. Radiolabbed BCEE irreversibly bound to protein was mainly found in the rat liver. Smaller amounts were found in kidney, small intestine, lung and spleen.

Executive summary:

The objective of this study was to evaluate the role of vinyl chloride metabolites (namely chloroethylene oxyde (CEO) an chloroacetaldehyde (CAA)) in the carcinogenicity of vinyl chloride (VC). 2,2' dichlorodiethyl ether (BCEE) was studied as a metabolite precusor of CAA. Following exposure to vapour of radiolabelled VC and BCEE, the distribution of radioactiviy in various tissues following covalent binding to protein was studied. The carcinogenic potential of exposure to these substance was evaluated by the occurrence of nucleic acid (RNA and DNA) alkylation and the potency of the two chemicals to induce preneoplastic ATPase-deficient foci in rat liver.

After 18 h exposure > 95% of the administered BCEE was taken up by the animals. Both chemicals displayed similar distribution in rat tissues. Radiolabbed BCEE irreversibly bound to protein was mainly found in the rat liver. Smaller amounts were found in kidney, small intestine, lung and spleen.