[2,9,16,23-tetrachloro-29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]copper

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well documented and acceptable study with the following restrictions: A 91 day subchronic dosed feed toxicity study was conducted in rats, similar to OECD Guideline 408 (Subchronic Oral Toxicity - Rodent: 90-day Study), but not a toxicokinetics study (similar to OECD Guideline 417). However, the study additionally included the examination of systemic copper absorption after exposure to the test material, analyzed in livers and kidneys of the animals.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1980

Report date:

1980

Reference 3

Reference Type:

other: expert judgement

Title:

Phthalocyanine Blue 15 B and Phthalocyanine Green 7

Author:

Mennear JH

Year:

1980

Bibliographic source:

Assessment from Dr. Mennear JH, Expert Toxicologist to Dr. Moore JA, Deputy Director NTP

Report date:

1980

Reference 4

Reference Type:

secondary source

Title:

Final SIDS Initial Assessment Profile on C.I. Pigment Green 7 Copper, [tetradecachloro-29H, 31 H-phthalocyaninato(2-)-N{29},N{30},N{31},N{32}]-

Author:

OECD

Year:

2005

Report date:

2005

Materials and methods

Objective of study:

distribution

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD Guideline 408 (Subchronic Oral Toxicity - Rodent: 90-day Study)

Deviations:

yes

Principles of method if other than guideline:

This subchronic toxicity study, similar to OECD Guideline 408, was conducted to assist in selecting Maximum Tolerated Dosages (MTD) for a 104 week chronic study in a dosed feed subchronic study. Additionally the study examined, whether or not systemic absorption of copper occured after exposure to the test material. Copper analyses were conducted in livers and kidneys of the animals.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32 copper

EC Number:

205-685-1

EC Name:

29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32 copper

Cas Number:

147-14-8

IUPAC Name:

[29H,31H-phthalocyaninato(2-)-kappa~2~N~29~,N~31~]copper

Details on test material:

- Name of test material (as cited in study report): Pigment Blue 15B
- Analytical purity: The chemical analysis, performed at Midwest Research Institute indicated that the purity was 104.7 % +- 1.1 % (elemental analysis)
- Elemental analysis indicated that the compound contained less than 0.01 % chlorine.

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Industries
- Weight at study initiation: males: 70 - 105 g; females: 70 - 100 g
- Housing: polycarbonate cages: groups of 5 rats per cage
- Diet: weighed portions of Purina Lab Chow in meal form, mixed together with weighed portions of the test material (see details at "doses/concentrations")
- Water: ad libitum
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21 - 23 °C
- Humidity: 40 - 60 %
- Air changes: at least 15 per hour
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: 12 % water was added to the test material as a dust control agent

Details on exposure:

Dose levels of 5.0, 2.5, 1.25, 0.6 and 0.3 % (w/w) were selected for both males and females. The selected doses were prepared by mixing weighed portions of purina Lab Chow in meal form with weighed portions of the test material. 12 % water was added to the test material as a dust control agent prior to mixing with the meal. For each dose level, one weekly lot of 4500 g (+ 12 % water compensation) was prepared.

The actual mixtures were composed of the following ingredients:
- Dose level 5.0 % (w/w): 252 g test material and water + 4275 g meal
- Dose level 2.5 % (w/w): 126 g test material and water + 4387.5 g meal
- Dose level 1.25 % (w/w): 63 g test material and water + 4443.75 g meal
- Dose level 0.6 % (w/w): 30.24 g test material and water + 44735 g meal
- Dose level 0.3 % (w/w): 15.12 g test material and water + 4486.5 g meal

Each diet was mixed in a Patterson-Kelly twin shelled V blender for 15 min.
The doses were mixed one or two days prior to the week of their use in the study, and stored at 23 °C.
One analysis was perfomed to determine the accuracy of the mixture concentration.

Duration and frequency of treatment / exposure:

90 days

Doses / concentrations

Remarks:

Doses / Concentrations:
Males and females: 0.3, 0.6, 1.25, 2.5, 5 % in diet; (approx. 0, 250, 500, 1100, 2200 and 4500 mg/kg bw for both sexes [based on 16.4 g/d average food consumption, 0.182 kg average bw for males and on 11.55 g/d average food consumption, 0.130 kg average bw] for females).

No. of animals per sex per dose / concentration:

10 males per dose and 10 females per dose

Control animals:

yes, plain diet

Details on study design:

The concentrations of the chemical mixture were the same for male and female rats. All dose levels were prepared on a weight per weight basis. There were 5 dose level groups with 10 individuals of each sex in each dosage and control group. Each dosed group received 90 consecutive days of dosed feed mixture. After one day of observation, the animals were necropsied. Animals were observed twice each day for clinical signs, with at least 6 hours between observations. All observations were recorded daily. Additionally, blood sampling was conducted from 10 control rats, 6 males and 4 females.

Copper analyses were completed in the liver and kidney tissues and the formalin preserving those tissues from male rats in the highest dose group (5 % w/w) and control groups:
- Tissue samples were prepared for analysis by digesting in 10 ml of concentrated nitric acid until most of the organic material was destroyed. Perchloric acid was then added and the solutions were evaporated to strong fumes, additional nitric acid being added as required. The solutions were then fumed to dryness, the residues were dissolved in 5 % nitric acid and the solutions were diluted to 10 ml.
- Formalin samples were filtered through a Millex-GS 0.22 µm filter unit and 5 ml portions of each sample were prepared for analysis by the procedure used to prepare the tissue samples.
- The samples were then subjected to atomic absorption spectrophotometry to determine copper content:
A Perkin-Elmer Model 5000 atomic absorption spectrophotometer was utilized for the work. A series of 10 ml standard solutions, ranging from 0.05 to 2.0 ppm were prepared in 5 % nitric acid by dilution of a certified standard copper stock solution. These solutions were used to calibrate the instrument, which was programmed to print out data as total microgramms of copper per sample. The prepared sample solutions were used in the same manner as the standards. Concentrations of copper in the tissue samples were calculated by dividing the total microgramms found by the weight of the sample. Concentrations of copper in the formalin samples were calculated on a volume basis.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (distribution)
- Tissues and body fluids sampled: liver and kidneys

Statistics:

Student´s T-test (alpha = 0.05) was used to compare the highest dose group results with control results.

Results and discussion

Main ADME results

Type:

absorption

Results:

No statistically significant increases of copper incorporation were reported in the liver and kidney tissues of treated male animals of the highest dose group compared to control animals.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

No statistically significant increase of residual copper incorporation was neither reported for the liver tissues (2.82 ppm +- 0.34 ppm) nor for the kidney tissues (5.62 ppm +- 0.49 ppm) of the treated male rats of the highest dose group, compared to residual copper incorporation found in controls (liver 2.78 ppm +- 0.51 ppm; kidney 5.30 ppm +- 0.83 ppm). From all the formalin analyses performed, the authors drawed the conclusion that no detectable levels of copper were leached from the preserved tissue into the formalin bath.

Metabolite characterisation studies

Details on metabolites:

No data given.

Any other information on results incl. tables

Table 1: Copper determinations in tissues and formalin of male rats from the subchronic study, treated with the test material for 90 days

male animal #	ppm copper
	liver	kidney	formalin	remark
highest dose group (5 % w/w)
1	4.6 - 4.3*	8.4	0.1	* results of 2 analyses
2	5.9	12.3	0.1
3	4.1 - 4.4*	8.6 - 10.1*	0.1	* results of 2 analyses
4	6.4	7.7	0.1
5	3.2	6.7	0.1
6	3.5	5.8	0.1
7	3.7	8.1	0.1
8	3.5 - 4.1	8.1	0.1
9	3.1	8.7 - 8.6*	0.1	* results of 2 analyses
10	4.6 - 4.5	7.2	0.1
control
1	3.1	3.7 - 4.0*	0.1	* results of 2 analyses
2	3.3	4.1	0.1
3	3.2	4.9 - 4.6*	0.1	* results of 2 analyses
4	3.7 - 4.0*	5.1	0.1	* results of 2 analyses
5	3.0	4.1	0.1
6	2.8	5.4	0.1
7	2.9	2.9 - 3.4*	0.1	* results of 2 analyses
8	2.6	5.5	0.1
9	2.6	5.4	0.1
10	3.3 - 3.6*	5.4	0.1	* results of 2 analyses

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results