Copper, [29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl derivs.

Basic toxicokinetics

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

Study period:

2014

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Objective of study:

other: distribution in plasma and liver

Principles of method if other than guideline:

Copper-content was determined in plasma and liver samples of rats that had been given gavage doses for 14 days at doses of 300 and 1000 mg/kg bw.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

[[2,2',2''-[29H,31H-phthalocyaninetriyltris(methylene)]tris[1H-isoindole-1,3(2H)-dionato]](2-)-N29,N30,N31,N32]copper

EC Number:

261-638-5

EC Name:

[[2,2',2''-[29H,31H-phthalocyaninetriyltris(methylene)]tris[1H-isoindole-1,3(2H)-dionato]](2-)-N29,N30,N31,N32]copper

Cas Number:

59160-79-1

Molecular formula:

C59 H31 Cu N11 O6

IUPAC Name:

[[2,2',2''-[(29H,31H-phthalocyanine-C,C,C-triyl-kN29,kN30,kN31,kN32)tris(methylene)]tris[1H-isoindole-1,3(2H)-dionato]](2-)]-copper

Test material form:

solid: nanoform

Details on test material:

BET: 17.5 m2/g
TEM (min. Feret): 46.2 nm (D50)

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sulzfeld, Germany
- Age at study initiation: 42 +/- 1 days
- Weight at study initiation:
- Fasting period before study: none
- Housing: single
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30 - 70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2014-06-09 To:2014-06-24

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: dnnkmg water containing 0.5% carboxymethylcellulose with about 5 mg/100 ml Cremophor EL

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Daily
The substance is a homogenous suspension.

Duration and frequency of treatment / exposure:

14 days

Doses / concentrations

Remarks:

Doses / Concentrations:
300 andd 1000 mg/kg bw

No. of animals per sex per dose / concentration:

5

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

A 14-day gavage study with an acid-labile copper-pigment (CAS 15680-42-9) was performed in the same year and this study showed a strong increase in liver copper content. (Plasma concentrations were not determined.)

Details on study design:

see endpoint study record for repeated dose toxcity

Details on dosing and sampling:

The determination of copper concentrations in EDTA plasma samples after were performed at the test facility.
The total concentrations of the test substance in plasma were calculated indirectly from the determined copper concentrations (inductively-coupled-plasma mass-spectrometry; experimental error + /- 0,2 mg/kg Cu).
This part of the study was carried out in compliance with the Principles of Good Laboratory Practice.
On study day 15, EDTA blood samples (about 200 μL) were collected from fasted animals by puncturing the retro-bulbar venous plexus under isoflurane anesthesia. After plasma preparation, the samples were frozen at about -80°C prior to analysis.

Liver samples were frozen at about -80°C prior to analysis.

Results and discussion

Main ADME results

Type:

other: distribution to liver and plasma

Results:

No increase in plasma and liver copper concentration was detected.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

No increase in plasma and liver copper concentration was detected (see tables 1 and 2).

Metabolite characterisation studies

Metabolites identified:

not measured

Applicant's summary and conclusion

Conclusions:

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

Executive summary:

Table 1: Copper content in liver samples

	animal no.	g liver	mg Copper	mg/g liver	mean (n = 5)
	1	2.043	0.011	5.38	5.54
males	2	2.021	0.011	5.44
control	3	2.2772	0.013	5.71
	4	1.9791	0.012	6.06
	5	1.9656	0.01	5.09
	6	2.2573	0.014	6.20	6.01
males	7	1.63	0.01	6.13
300 mg/kg bw	8	1.5929	0.008	5.02
	9	2.0888	0.012	5.74
	10	2.0201	0.014	6.93
	11	2.1328	0.011	5.16	5.31
males	12	1.9677	0.011	5.59
1000 mg/kg bw	13	1.2978	0.007	5.39
	14	1.977	0.011	5.56
	15	2.4663	0.012	4.87
	16	1.3527	0.008	5.91	6.15
females	17	1.2401	0.008	6.45
control	18	1.2873	0.008	6.21
	19	1.3878	0.008	5.76
	20	1.2479	0.008	6.41
	21	1.245	0.008	6.43	6.41
females	22	1.1989	0.008	6.67
300 mg/kg bw	23	1.3348	0.009	6.74
	24	1.5306	0.009	5.88
	25	1.2649	0.008	6.32
females	26	1.2009	0.007	5.83	6.16
1000 mg/kg bw	27	1.2749	0.009	7.06
	28	1.2284	0.007	5.70
	29	1.3773	0.008	5.81
	30	1.2447	0.008	6.43

Table 2: Copper content in plasma samples

	animal no.	mg/kg	mean
	1	1	1.28
males	2	1.3
control	3	1.3
	4	1.1
	5	1.7
	6	2.1	1.48
males	7	1.1
300 mg/kg bw	8	1.5
	9	1.2
	10	1.5
	11	1.5	1.4
males	12	1.1
1000 mg/kg bw	13	1.5
	14	1.4
	15	1.5
	16	1	1.18
females	17	1
control	18	1.3
	19	1.1
	20	1.5
	21	1.5	1.4
females	22	1.1
300 mg/kg bw	23	1
	24	1.5
	25	1.9
females	26	1.3	1.52
1000 mg/kg bw	27	2.3
	28	1
	29	1.1
	30	1.5