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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
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 mice, 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

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report date:
1980
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 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)
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

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.
-Structure: see figure
Radiolabelling:
no

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Industries
- Age at study initiation: 8.5 weeks
- Weight at study initiation: males: 16 - 23 g; females: 16 - 19 g
- Housing: polycarbonate cages: groups of 5 mice 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, 1000, 2000, 4000, 8000 and 16000 mg/kg bw for males [based on 7.3 g/d average food consumption, 0.023 kg average bw] and approx. 0, 1100, 2200, 4700, 9400 and 18700 mg/kg bw for females [based on 7.1 g/d average food consumption, 0.019 kg average bw], respectively).
No. of animals per sex per dose / concentration:
10 males and 10 females per dose
Control animals:
yes, plain diet
Details on study design:
- 10 animals were used per sex and dose group.
- Five dose levels of 0.0, 0.3, 0.6, 1.25 and 5.0 % in feed were used in this study (approx. 1000, 2000, 4000, 8000 and 16000 mg/kg bw for males [based on 7.3 g/d average food consumption, 0.023 kg average bw] and approx. 1100, 2200, 4700, 9300 and 18700 mg/kg bw for females [based on 7.1 g/d average food consumption, 0.019 kg average bw], respectively).
- The selected doses were prepared by mixing together weighed portions of Purina Lab Chow in meal form with weighed portions of the chemical. 12% water was added to the chemical as a dust control agent prior to mixing with the meal.
- Each dosed group received on 91 consecutive days of dosed feed mixture.
- Mice were necropsied on day 92 and 93.

Copper analyses were completed in the liver and kidney tissues and the formalin preserving those tissues from male mice 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.
Statistics:
Student´s T-test (alpha = 0.05) was used to compare the highest dose group results with control results.

Results and discussion

Preliminary studies:
No data given.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No data given.
Details on distribution in tissues:
Slight, but statistically significant increases of copper incorporation were reported in the liver tissues (3.98 ppm +- 1.16 ppm; p < 0.05) and kidney (7.47 ppm +- 2.86 ppm; p < 0.05) tissues of treated male animals of the highest dose group, compared to controls (liver: 3.0 ppm +- 0.34 ppm; kidney: 4.66 ppm +- 0.6 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.
However, an evaluation of the results was conducted by expert judgement and the author draw the following conclusions:
The results of the study do not provide unequivocal evidence for a lack of absorption of the test material. However, the total lack of findings during the 13 week study, coupled with the insolubility of the test material and the minimal changes in tissue copper residues strongly suggests that the test material was not appreciably absorbed.
Details on excretion:
No data given.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
No data given.

Any other information on results incl. tables

Table 1: Copper determinations in tissues and formalin of male mice from the subchronic study, treated with the test material for 91 days

male animal #

ppm copper

 

 

liver

kidney

formalin

remark

highest dose group (5 % w/w)

 

 

 

 

1

7.0

14.5

--

 

2

3.2-3.6 *

6.8

--

* results of 2 analyses

3

3.4

7.7

--

 

4

3.4

4.8

--

 

5

3.5

6.3

--

 

6

3.7

7.3

--

 

7

3.9

6.4

--

 

8

4.1

8.2

--

 

9

3.3-3.6 *

5.2

--

* results of 2 analyses

control

 

 

 

 

1

3.5

4.2

0.1

 

2

3.1

3.8

0.1

 

3

3.1

4.6

0.1

 

4

2.8

4.6

0.1

 

5

2.9

4.2

0.1

 

6

3.2

4.7

0.1

 

7

3.2

5.8

0.1

 

8

2.9

5.3

0.1

 

9

2.3

4.7

0.1

 

Applicant's summary and conclusion

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