Reaction product of Chloro[29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]aluminium, sulphuric acid and caustic soda

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Remarks:

Elimination after intravenous administration

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Reason / purpose for cross-reference:

reference to same study

GLP compliance:

no

Remarks:

Study pre-dates GLP regulations

Specific details on test material used for the study:

- Name as used in the study report: Tinolux 4204

Radiolabelling:

yes

Species:

guinea pig

Strain:

other: Tif:DHP

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CIBA-GEIGY animal farm
- Age at study initiation:42-56 days
- Weight at study initiation: 310-410 g
- Housing: individually in metabolic cages
- Diet: standard guinea pig pellets - NAFAG No. 830
- Water: not specified
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS: not specified

Type of coverage:

occlusive

Vehicle:

water

Duration of exposure:

- first experiment: 30 minutes
- second experiment: 6 hours

Doses:

0.05 ml of an aqueous solution containing 1 mg of the substance was applied topically

No. of animals per group:

- Two animals in the group of 30 minutes exposure
- Three animals in the group of 6 hours exposure

Control animals:

no

Details on study design:

24 hours before topical application an area of 3.6 x 3.6 cm = 13 cm2 of dorsal skin was shaved to 1/20 mm hair length. Onto this area 0.05 ml of an aqueous solution containing 1 mg of the substance were applied evenly with a syringe. The application site was covered with a layer of OCLUFOL which was fixed with ISOELAST. In the first experiment (animal A and B) the occlusive dressing was removed 30 min after application. The dressing covering the treated area was cut off and placed in 1000 ml water. The unabsorbed preparation remaining on the surface of the skin at the application site was removed by wiping it off with ten 2 x 2.2 cm cellulose tissue swabs moistened with water, the swabs were extracted in the same water where the occlusive clothing was placed.
In the second experiment (animals C,D and E) the occlusive dressing was removed in the same way 6 h after application.
Radioactivity was measured using a liquid scintillation counter by using the following procedures:
- Blood : 0.3 ml of blood was treated with 2 ml of a 1:1 mixture of IRGASOLV (CIBA-GEIGY) and isopropanol followed by the addition of 0.5 ml of 25% aqueous hydrogen peroxide. After 15 min at room temperature 0.5 ml of 2 N HCl and 16.5 ml of IRGASCINT A 300 (CIBA-GEIGY) were added.
- Tissues: Samples of up to 200 mg were left overnight with 2 ml of IRGASOLV at 40*'c, then 0.5 ml of 2 N HCl and 17.5 ml of IRGASCINT A 300 were added.
- Urine: Samples of 0.3 ml were diluted with 20 ml of IRGASCINT A 300 (CIBA-GEIGY Ltd.).
- Faeces: Faeces were homogenized after the addition of about the same amount of water, samples of 70-200 mg of the homogenates were left with 2 ml of a solution of 1:1 IRGASOLV in isopropanol for 4 h at 40 C, then 1 ml undiluted IRGASOLV was added and the mixture kept overnight at 40 C. After that 0.5 ml 2 N HCl and 16.5 ml IRGASCINT A 300 were added.
Sample counts were corrected for quenching by means of an external calibration curve. They were expressed as concentrations of unchanged substance using the specific radioactivity of the labelled substance. This was determined for each sample series by simultaneously measuring standard samples of known concentrations.

Signs and symptoms of toxicity:

not examined

Dermal irritation:

not examined

Absorption in different matrices:

After an exposition time of 30 min and 6 h the excretion was about similar. Up to 168 h about 1% of the administered radioactivity was eliminated in the urine and about 5% in the faeces. Thus about 6% of the topically applied dose was absorbed through the skin. The elimination was slow and not finished after 168 h. 144 h and 168 h after administration a relatively large portion of the dose was still found in the skin at the application site. Results suggest that the amounts taken up by the skin are independent of the exposition time. The concentrations measured for blood, plasma, liver, kidney, muscle and white fat were at or below the significant detection limit. Measurable, but low 14C-concentrations of 0.01-0.08 ug/g were found in the liver. The mean of 0.042 µg/g corresponds to 0.05 % of the dose, calculated for a liver weight of 16 g.

Key result

Time point:

168 h

Dose:

1 mg

Parameter:

percentage

Absorption:

ca. 6 %

Remarks on result:

other: Similar results were obtained for exposition times of 30 min and 6 h.

The authors conclude that the absorption is 6% based on the amount excreted, but as can be observed in the same test using i.v. exposure within 168 hours only 50% of the test substance is excreted. As a result, the absorption would be around 12%.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

A solution of the radio-labeled substance was applied by intravenous administration and distribution in the body and excretion was measured up to 168 h

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Aluminum, hydroxy[29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, chloro sulfo derivs., sodium salts

EC Number:

307-259-1

EC Name:

Aluminum, hydroxy[29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, chloro sulfo derivs., sodium salts

Cas Number:

97592-62-6

Molecular formula:

not available

IUPAC Name:

Aluminum, hydroxy[29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, chloro sulfo derivs., sodium salts

Test material form:

solid

Specific details on test material used for the study:

- Name as used in the study report: Tinolux 4204

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

other: Tif:RIAf (SPF)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CIBA-GEIGY animal farm
- Age at study initiation: 54 days
- Weight at study initiation: 250 g
- Housing: individually in metabolic cages
- Diet: NAFAG pellets No. 890
- Water: not specified
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS: not specified

Administration / exposure

Route of administration:

intravenous

Vehicle:

physiological saline

Details on exposure:

The substance was dissolved in 0.6 ml 0.9% NaCl-solution and injected into the tail vein; 2 mg/kg dose

Duration and frequency of treatment / exposure:

single injection

Doses / concentrations

Dose / conc.:

2 mg/kg bw/day

No. of animals per sex per dose / concentration:

2

Control animals:

no

Positive control reference chemical:

no

Details on study design:

The animals were housed singly in metabolic cages constructed of stainless steel and glass and designed to separate urine and faeces. Urine was collected 6 h after dosing and thereafter urine and faeces were quantitatively collected daily up to 144 h and 168 h respectively.

Radioactivity was measured using a liquid scintillation counter by using the following procedures:
- Blood : 0.3 ml of blood was treated with 2 ml of a 1:1 mixture of IRGASOLV (CIBA-GEIGY) and isopropanol followed by the addition of 0.5 ml of 25% aqueous hydrogen peroxide. After 15 min at room temperature 0.5 ml of 2 N HCl and 16.5 ml of IRGASCINT A 300 (CIBA-GEIGY) were added.
- Tissues: Samples of up to 200 mg were left overnight with 2 ml of IRGASOLV at 40*'c, then 0.5 ml of 2 N HCl and 17.5 ml of IRGASCINT A 300 were added.
- Urine: Samples of 0.3 ml were diluted with 20 ml of IRGASCINT A 300 (CIBA-GEIGY Ltd.).
- Faeces: Faeces were homogenized after the addition of about the same amount of water, samples of 70-200 mg of the homogenates were left with 2 ml of a solution of 1:1 IRGASOLV in isopropanol for 4 h at 40 C, then 1 ml undiluted IRGASOLV was added and the mixture kept overnight at 40 C. After that 0.5 ml 2 N HCl and 16.5 ml IRGASCINT A 300 were added.

Statistics:

Sample counts were corrected for quenching by means of an external calibration curve. They were expressed as concentrations of unchanged substance using the specific radioactivity of the labelled substance. This was determined for each sample series by simultaneously measuring standard samples of known concentrations. Sample counts equal to or less than Ib+ Δn (Δn calculated according the formula below [1]) were considered not to differ significantly from the background value Iband were not further processed.) Δn = 3 √ Ib(1/ts+ 1/ tb) [1] with Δn = detection limit (cpm); Ib= background (cpm); ts= sample counting time (min); tb= background counting time (min).

Results and discussion

Main ADME results

Type:

excretion

Results:

up to 168 h only 50% of the intravenously administered radioactivity was recovered with urine (15%) and faeces (35%) .

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Highest concentrations were found in the liver (15.4 µg/g) and spleen (7.7 µg/g), the lowest ones in the blood and muscle (0.1µg/g) and the brain (0.02 µg/g) .
According to these concentrations 168 h after dosing about 46% of the dose was still in the body with the major fraction in the liver (35% of the dose).

Details on excretion:

up to 168 h only 50% of the intravenously administered radioactivity was recovered with urine (15%) and faeces (35%) .

Metabolite characterisation studies

Metabolites identified:

not measured