1,1-dichloroethylene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well conducted with a suited monitoring of the radioactivity. In accordance with the OECD guideline 417.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1978

Materials and methods

Objective of study:

distribution

excretion

metabolism

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

1,1-dichloroethylene

EC Number:

200-864-0

EC Name:

1,1-dichloroethylene

Cas Number:

75-35-4

Molecular formula:

C2H2Cl2

IUPAC Name:

1,1-dichloroethene

Details on test material:

- Name of test material (as cited in study report): vinylidene chloride
- Physical state: liquid
- source: Imperial Chemical Industries Ltd., Mond Division, Runcorn, Cheshire
- stabiliser was removed by washing with alkali and water

[1-14C] vinylidene chloride and [2-14C] vinylidene chloride were synthetised
- specific activity: 1.0 mCi/mmol
- chemical and radiochemical purity: > 99.0 %
- stored as a solution in peroxide-free corn oil at -20 °C

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

other: Alderley Park strain (Wistar-derived)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approximatively 2 months
- Weight at study initiation: 200 g
- Individual metabolism cages: yes
- Diet: standard pellet diet ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

Different experiments were conducted:
* excretion-retention experiments:
- single dose of [2-14C]vinylidene chloride (either 500 pg/kg or 350 mg/kg; 1 µCi) as a corn-oil solution administered via the intragastric, intravenous and intraperitoneal routes.
- an intragastric dose of [1-,14C]vinylidene chloride (350 mg/kg; 15 µCi) as a corn-oil solution

*Identification of urinary metabolites, groups of 4 animals were dosed intragastrically :
- [14C]vinylidene chloride (350 mg/kg; 10 µCi per animal) in corn-oil solution
- an aqueous solution of L-[U-14C] cysteine hydrochloride with a 17 h interval (total dose, approx. 50 µCi). 2 h after the second injection, each animal was given a single intragastric dose of vinylidene chloride (350 mg/kg) in corn-oil solution
- 2 intraperitoneal injections of an aqueous solution of 20 µCi of L-[U-14C]cysteine hydrochloride and 20 µCi of [U-14C]glycine with an 18 h interval. 1 h after the second injection, each animal was given a single intragastric dose of vinylidene chloride (350 mg/kg) in corn-oil solution

*Distribution :
an intragastric dose of 20 µCi of [14C]vinylidene chloride

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
500 µg/kg
350 mg/kg

No. of animals per sex per dose / concentration:

4

Control animals:

no

Positive control reference chemical:

No

Details on study design:

* Excretion-retention experiments:
- groups of 4 animals were administered single doses of [2-14C]vinylidene chloride (either 500 pg/kg or 350 mg/kg; 1 µCi) as a corn-oil solution by the intragastric, intravenous and intraperitoneal routes.
- 3 rats, equipped with a biliary fistula, were each given an intragastric dose of [1-,14C]vinylidene chloride (350 mg/kg; 15 µCi) as a corn-oil solution, and they were maintained in restraining cages for 48 h, during which time bile and urine were collected.

* Identification of urinary metabolites, groups of 4 animals were administered intragastrically:
- [14C]vinylidene chloride (350 mg/kg; 10 µCi per animal) in corn-oil solution
- 2 rats given 2 intraperitoneal injections of an aqueous solution of L-[U-14C] cysteine hydrochloride with a 17 h interval (total dose, approx. 50 µCi). 2 h after the second injection, each animal was given a single intragastric dose of vinylidene chloride (350 mg/kg) in corn-oil solution, and the 48 h urine was collected.
- 2 rats were each administered 2 intraperitoneal injections of an aqueous solution of 20 µCi of L-[U-14C]cysteine hydrochloride and 20 µCi of [U-14C]glycine with an 18 h interval. 1 h after the second injection, each animal was given a single intragastric close of vinylidene chloride (350 mg/kg) in corn-oil solution, and the 48 h urine was collected.

* Distribution:
Young rats (about 80 g body weight) were administered an intragastric dose of 20 µCi of [14C]vinylidene chloride.

Details on dosing and sampling:

* Excretion-retention experiments:
The animals were single-housed in glass metabolism cages for 72 h after administration, and 14C was measured in the urine, faeces and exhaled air, which was drawn successively through trichloroethylene at -70 °C and CO2 absorbers

* Distribution:
30 min, 60 min and 2 days after administration, the animals were deeply anaesthetised and were rapidly frozen by immersion in solid C02. Longitudinal sagittal sections, 20 µm in thickness, were cut with a mechanically operated Cambridge microtome, in a Bright cryostat at -20 °C; some were cut through the vertebrae and others through a kidney of each animal. Apposition autoradiograms were prepared from the freeze-dried sections.

* Analytical methods:
- Measurement of radioactivity:
Intertechnique Model SL30 liquid scintillation spectrometer
Liquid samples were admixed with standard scintillator and radioassayed directly
Samples of faeces were burnt in an Intertechnique "Oxymat" solid-sample oxidizer before measurement

- Systematic separation of the urinary metabolites into fractions of chemically similar substances (Identification of urinary metabolites experiments):
Urine from each group of rats was separated into 3 fractions by anion-exchange chromatography. The 3 N HCl fractions were evaporated separately to dryness under reduced pressure, and the various residues were methylated with an ethereal solution of diazomethane. Methanolic solutions of the resulting O-methyl esters were analysed on gas chromatography (GC) columns and in the GC-mass spectrometer system. The neutral fractions and the 3 N acetic acid fractions were also evaporated separately to dryness under reduced pressure, and the different residues were examined by thin layer chromatography. After esterification with diazomethane or butan-1-ol and acylation with trifluoroacetic anhydride, the individual compounds, in the residues resulting from the evaporation of the acid hydrolyates of the last two fractions, were analysed on GC columns and in the GC-mass spectrometer system.

- Thin-layer chromatography:
The material eluted from the anion exchange column with 3 N acetic acid was applied as bands on 500 µg SiO2 gel GF thin-layer plates which were developed with butan-1-ol-acetic acid-water (4 : 1 : 2). Zones of 14C were located with a Panax TLC scanner, excised and eluted with methanol.

- Gas chromatography:
Fractions containing radioactive metabolites were examined with a Pye Model 104 instrument that was equipped with flame-ionization detection and that was coupled to an E.S.I. Nuclear 504 Radiogas detector. The column effluent was split in the ratio of 10:1 between the Radiogas detector and the flame-ionization detector. This gas chromatograph was fitted with glass columns (2.1 m long X 4 mm int. diam.) which were packed with 6 % (w/w) OV-101 on Supelcoport (80-100 mesh size) and run at 100 °C and 180 °C. GC analysis was also used for the identification of unchanged vinylidene chloride which had been collected from the exhaled air in cold traps containing 1,1,2 trichloroethylene. In that case, the gas chromatograph was fitted with glass columns (1.5 m long X 4 mm int. diam.) which were packed with 10 % (w/w) squalene on Chromosorb P (80-100 mesh size) and run at 80 °C. All of the columns were operated at a 40 mL/min flow-rate of a (95 : 5 v/v) Ar-CO2 mixture. Radioactive peaks were located and the corresponding samples were analysed by GC-mass spectrometry using the same columns under identical operating conditions.

-GC-mass spectrometry :
An LKB2091 gas chromatograph-mass spectrometer system was used for the E.I. spectra of the compounds

Statistics:

No data

Results and discussion

Preliminary studies:

No data

Toxicokinetic / pharmacokinetic studies

Details on absorption:

No data

Details on distribution in tissues:

Sequential autoradiograms of longitudinal sagittal sections through whole animals which had been administered intragastrically [14C] vinylidene chloride show large 14C concentrations in the kidneys and liver after 30 min and a more general distribution of 14C throughout the soft organs of the body at 1 h. The kidneys and liver retain 14C for the longest times after administration.

Details on excretion:

In every case except one, almost all of the radioactivity was recovered during the first 72 h after dosing, but after low intragastric administration, small amounts of 14C were still being excreted (Table 1).
Higher dose : nearly 70 % as unchanged vinylidene chloride and 1 % of CO2 are excreted via the lungs
Lower dose : urinary excretion accounts for 80 %, and less than 1 % of unchanged vinylidene chloride together with 4-6 % of C02 are eliminated by the pulmonary route
About 210 times more vinylidene chloride was metabolized at the higher dose level than at the lower one
80 % of a small intravenous dose of vinylidene chloride is excreted unchanged from systemic blood within an hour of injection; more than 60 % within 5 min
Via intragastric administration, some of the vinylidene chloride is taken up into systemic blood and is excreted unchanged via the lungs and some is absorbed into the hepatic-portal system and is metabolised by the liver.
Unchanged vinylidene chloride was the only product excreted via the lungs.
The origin of the urinary radioactivity was biliary (Table 2).

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

See Table 3

Any other information on results incl. tables

Table 1: excretion of radioactivity in rats given a single dose of [14C] vinylidene chloride

Radioactivity excreted (% of dose) (mean±SD)

Intragastric

Intravenous

Intraperitoneal

Exhaled air

Urine

Faeces

Exhaled air

Urine

Faeces

Exhaled air

Urine

Faeces

Dose

Time (h)

Vinylidene chloride

CO2

Vinylidene chloride

CO2

Vinylidene chloride

CO2

500 µg/kg

0-24

0.6±0.2

3.9±0.7

71.3±1.2

5.1±0.7

80.4±0.4

3.5±0.6

14.4±3.6

0.3

11.4±2.8

2.6±0.7

65.8±2.5

14.2±4.4

24-48

0.06

0.5±0.4

5.3±0.9

2.7±0.9

0

0

0.7±0.2

0.1

0.2

0.5±0.1

2.0±0.1

1.6±1.1

48-72

0.08

0.5±0.2

3.6±1.7

0.6±0.2

0

0

0

0

0.1

0.5±0.2

1.2±0.3

0.4

Total

0.7±0.1

4.8±1.3

80.2±1.4

8.3±0.1

80.0±0.4

3.5±0.6

15.0±3.9

0.4

11.7±2.8

3.6±0.7

69.0±2.8

16.2±4.5

350 mg/kg

0-24

62.4±4.3

0.3

17.6±4.4

0.4

90.5±2.9

0.7±0.4

7.1±2.1

0.5±0.2

24-48

4.8±2.8

0.4

10.0±4.0

0.5±0.3

0.6±0.3

0.5±0.2

0.3

0.1

48-72

0.1

0.3

1.9±1.0

0.4

0

0.1

0.3

0.1

Total

67.3±4.3

1.0±0.1

29.5±6.7

1.3±0.4

91.1±3.2

1.3±0.6

7.7±2.1

0.7±0.3

Table 2: excretion of 14C in the urine and bile after an intragastric dose of [14C] vinylidene chloride (350 mg/kg)

	Recovery of 14C (% of dose)
	0-3h	3-6h	6-24h	24-48h
Normal rats Urine	0	2.9±0.9	15.8±1.8	3.1±1.0
Rats equipped with biliary fistula Urine	0	0.2±0.1	6.5±0.5	2.4±0.4
Bile	0.9±0.7	2.1±0.3	5.9±1.7	2.4±0.6

Table 3: proportion of the urinary metabolites of vinylidene chloride in rats

Vinylidene chloride urinary metabolites	% of urinary radioactivity
Thiodiglycollic acid	37.0
N-Acetyl-S-cysteinyl-acetyl derivative	48.0
Dithioglycollic acid	5.0
Thioglycollic acid	3.0
Chloroacetic acid	3.0
Urea	0.5
S-(Carboxymethyl)cysteine	0

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The main route of elimination of 1,1-dichlorethene is via lungs (unchanged 1,1-dichloroethene). Also the liver (bile) and kidneys are involved in the excretion of 1,1-dichloroethene.

Executive summary:

The biological fate of vinylidene chloride was studied in rats after a single intravenous, intragastric or intraperitoneal administration of [14C]compound. The main route of elimination of 1,1-dichlorethene after intraveneous adminstration is via lungs. Pulmonary (unchanged vinylidene chloride) and urinary (metabolites, a part of which are of biliary origin) excretions after a single oral administration are completed within 3 days. Orally, about 80 % of a low dose (500 µg/kg) is excreted in urine whereas 67 % of a high dose (350 mg/kg) is excreted unchanged by lungs. The major urinary metabolites are the thiodiglycollic acid and an N-acetyl-S-cysteinyl-acetyl derivative. The liver and kidneys are the major organs exposed to radioactive compounds.