[1,3,8,16,18,24-hexabromo-2,4,9,10,11,15,17,22,23,25-decachloro-29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]copper

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Peer reviewed well documented study.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

; no clinical chemistry, hematology, or urinalysis were conducted and no organ weights were taken (as recommended in OECD Guideline 408).

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Polychloro copper phthalocyanine

EC Number:

215-524-7

EC Name:

Polychloro copper phthalocyanine

Cas Number:

1328-53-6

Molecular formula:

C32 Hx Cly Cu N8, x+y=16

IUPAC Name:

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

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): Pigment Green 7, C.I. 74260

Specific details on test material used for the study:

- Name of test material (as cited in study report): Phthalocyanine Green 7
- Analytical purity: 97.8 %
Green 7 (Phthalocyanine Green) manufactured by Dry Color Manufacturers' Association, was obtained from Midwest Research institute on March 28, 1978. The elemental analysis pcrfortied at Midwest Research Institute was low for copper and nitrogen, slightly low for carbon, and slightly high for hydrogen and chlorine; values for all determined elements totaled 97.8 percent.

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Harlan Industries
- Age at study initiation: 8.5 weeks
- Weight at study initiation: males: 20 - 24 g; females: 15 - 18 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:

unchanged (no vehicle)

Details on oral 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): 225 g test material and water + 4275 g meal
- Dose level 2.5 % (w/w): 112.5 g test material and water + 4387.5 g meal
- Dose level 1.25 % (w/w): 56.25 g test material and water + 4443.75 g meal
- Dose level 0.6 % (w/w): 27 g test material and water + 44735 g meal
- Dose level 0.3 % (w/w): 13.5 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.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

One analysis was perfomed to determine the accuracy of the mixture concentration. Results were within +- 10 % of the desired dose concentration.

Duration of treatment / exposure:

91 days

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.3 other: % in the diet

Doses / concentrations 2

Dose / conc.:

0.6 other: % in the diet

Doses / concentrations 3

Dose / conc.:

1.25 other: % in the diet

Doses / concentrations 4

Dose / conc.:

2.5 other: % in the diet

Doses / concentrations 5

Dose / conc.:

5 other: % in the diet

No. of animals per sex per dose:

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, 2.5 and 5.0 % in feed were used in this study (approx. 0, 1000, 2000, 4000, 8000 or 16000 mg/kg bw/day for males, [based on 8.2 g/d average food consumption, 0.026 kg average bw] and approx. 0, 1200, 2500, 5000, 10000 and 20000 mg/kg bw/day for females [based on 7.7 g/d average food consumption, 0.019 kg average bw]).
- The selected doses were prepared by mixing together weighed portions of Purina Lab Chow in meal form with weighed portions of the chemical.
- Each dosed group received dosed feed mixture on 91 consecutive days.

Examinations

Observations and examinations performed and frequency:

Animals were observed twice each day for clinical signs, with at least 6 hours between observations. All clinical signs were recorded daily. Additional studies included blood sampling for the animal disease screening program from 10 control mice, 5 males and 5 females.

Sacrifice and pathology:

Mice were necropsied on day 92 and 93.
- Gross examination were performed on all animals from all dosage groups.
- Microscopic examinations were performed on following organs from all animals in the control group and the highest dose treatment group: Kidney, liver, lung, heart, epididymis, stomach, thyroid, skin (only in control group: bone marrow, urinary bladder, testis).

Other examinations:

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. See details and results in endpoint "7.1.1. Basic toxicokinetics"

Results and discussion

Results of examinations

Details on results:

- MORTALITY:
4 deaths occurred during the study; 3 males at 1.25 % and 1 control male. These deaths were not considered to be test substance related. There were no early dead females during the course of the study.

- CLINICAL SIGNS:
No treatment related abnormal clinical signs were observed.

- FOOD CONSUMPTION:
There were no trends in diet consumption among dosed animals compared with controls in either male or female mice. Average daily consumption
among male mice dosed groups and controls ranged from 7.6-9.5 g; female mice dosed groups and controls ranged from 7.5 to 7.8 g. While male ranges were somewhat erratic, there was no indication of dose-related effects.

- BODY WEIGHT:
A -9 % to +8 % differential weight gain was seen in the dosed females. Animals in the highest dose levels had less weight gain than controls. However, given the normal variability in mouse body weight measurements, this differences did not necessarily reflect a manifestation of toxicity. Dosed male mouse groups showed a positive weight differential in all groups except the 0.6 % dosage group. In this group during week 12 with a corresponding weight loss was observed, which was not fully recovered during the final week of the study.

- PATHOLOGY:
No substance related changes were reported on macroscopic and microscopic examination of the animals. Gross examination were performed on all animals from all dosage groups. The microscopical lesions found were encountered in both the control and experimental high dose group with similar frequency and severity.

A dosage level of 5 % and 2.5 % was recommended to be used test substance in the chronic study, due to lack of compound-related lesions.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

ca. 16 000 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: no adverse effects observed

2

Dose descriptor:

NOAEL

Effect level:

ca. 20 000 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: no adverse effects observed

Target system / organ toxicity

Critical effects observed:

no