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

Endpoint summary

Description of key information

A related substance did not induce skin sensitization in the LLNA (BASF 2014).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

CBA

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River UK
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 17.8 - 20.5 g
- Housing: all animals in one group were housed in a cage together as a group
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 45 – 65%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2015-06-05 To 2014-07-01

Vehicle:

propylene glycol

Concentration:

2, 5 and 10% (w/w)

No. of animals per dose:

5

Details on study design:

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: standard H-Methylthymidine incorporation
- Criteria used to consider a positive response: SI > 3

TREATMENT PREPARATION AND ADMINISTRATION: Each test group of mice was treated by topical (epidermal) application to the dorsal surface
of each ear. The application volume, 25 μL/ear/day, was spread over the entire dorsal surface (diameter 8 mm) of each ear once daily for three consecutive days. A further group of mice (control animals) was treated with an equivalent volume of the relevant vehicle alone.

Positive control substance(s):

hexyl cinnamic aldehyde (CAS No 101-86-0)

Positive control results:

SI = 13.7%
The periodic positive control experiment was performed in April 2014
Positive control substance: α-Hexylcinnamaldehyde; Vehicle: acetone:olive oil (4+1 v/v)

Parameter:

SI

Value:

1.24

Test group / Remarks:

10%

Parameter:

SI

Value:

0.95

Test group / Remarks:

5%

Parameter:

SI

Value:

0.69

Test group / Remarks:

2%

Table 1: Lymph Node Cell Counts after Sacrifice

Test item concentration % (w/w)	Animal No.	Lymph Node Cell Count x10E06 per animal	Mean Lymph Node Cell Count x10E06 per animal	SD	Index (Value Test Group versus Value Control
Vehicle Control (PG)	1	7.65	8.4	1.4	1.00
	2	7.99
	3	9.45
	4	10.18
	5	6.61
2	6	6.84	6.9	1.3	0.82
	7	6.42
	8	5.01
	9	8.30
	10	7.86
5	11	8.67	7.1	2.4	0.85
	12	7.99
	13	8.56
	14	7.29
	15	2.95
10	16	7.45	9.2	1.6	1.10
	17	10.13
	18	7.65
	19	10.91
	20	10.00

Table 2: Lymph Node Weights after Sacrifice

Test item concentration % (w/w)	Animal No.	Lymph Node weight mg per animal	Mean Lymph Node weight (mg)	SD	Index (Value Test Group versus Value Control
Vehicle Control (PG)	1	4.67	4.7	0.5	1.0
	2	4.47
	3	5.09
	4	5.30
	5	4.09
2	6	4.39	4.3	0.5	0.9
	7	4.41
	8	3.39
	9	4.46
	10	4.75
5	11	4.92	3.9	1.3	0.83
	12	4.72
	13	4.25
	14	4.11
	15	1.63
10	16	4.19	5.4	0.9	1.14
	17	6.41
	18	4.88
	19	6.27
	20	5.22

Table 3: Ear Weights after Sacrifice

Test item concentration % (w/w)	Animal No.	Ear weight mg per animal	Mean Ear weight (mg)	SD	Index (Value Test Group versus Value Control)
Vehicle Control (PG)	1	23.74	24.4	0.9	1.00
	2	24.87
	3	25.81
	4	23.78
	5	23.95
2.0%	6	23.89	23.2	0.6	0.95
	7	22.44
	8	23.60
	9	23.09
	10	22.80
5%	11	23.29	25.6	2.5	1.05
	12	24.89
	13	29.90
	14	25.25
	15	24.81
10%	16	27.50	27.1	0.8	1.11
	17	26.10
	18	28.34
	19	26.87
	20	26.85

No signs of systemic toxicity or local skin irritation were observed during the study period. A possible erythema of the ear skin could not be evaluated due to the inherent colour of the test item.

The body weight of the animals, recordedprior to the first application and prior to treatment with³HTdR, was within the range commonly recorded for animals of this strain and age.

A statistically significant increase in ear weights was observed in the high dose group in comparison to the vehicle control group (p<0.05). Furthermore, for BALB/c mice, a cut-off value of 1.1 for the ear weight index was reported for a positive response regarding ear skin irritation (see Ref. 9). The index determined for the test item treated high dose group slightly exceeded this threshold (index of 1.11). However, this was considered to be not biologically relevant, as the observed increase did not exceedthe threshold value of 25% for excessive local skin irritation mentioned in OECD guideline 429. Nevertheless, the increased ear weights indicated an irritant property of the test item.

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

No experimental data is available for the substance itself, but the UVCB analogue with the slightly average substitution grade (2.48 versus 1.4) has been tested. Both substances share the same components; the analogue UVCB substance contains more of the higher substituted components. All components are poorly soluble and have a molecular weight greater than 500 g/mol and have a poor potential for skin permeability. The adverse outcome pathway for skin sensitization begins is based on the molecular initiating event of protein binding. In this case, the structural features are identical and any potential for protein reactivity present in the target substance would be identified from the higher substituted analogue.  In addition, neither the phtthalocyanine core nor the phthalimide substitutent on their own are skin sensitizers (see data matrix). Therefore, it is acceptable to use the data of the analogue for read-across.

The analogue with the higher average substitution grade (CAS 59160 -79 -1) was assessed for its skin sensitising potential using the Local Lymph Node Assay (LLNA) in mice. That study fulfilled all validity criteria in that it followed the OECD guideline 429 and was performed under GLP. Test item suspension at different concentrations was prepared in the vehicle propylene glycol. The local lymph node assay was performed using test item concentrations of 2, 5, and 10% (w/w). The highest concentration tested was the highest concentration that could be achieved whilst avoiding systemic toxicity and excessive local skin irritation (as determined by a pre-experiment). The animals did not show any signs of systemic toxicity or local skin irritation during the course of the study and no cases of mortality were observed. A possible erythema of the ear skin could not be evaluated due to the inherent colour of the test item. Stimulation Indices (S.I.) of 0.69, 0.95 and 1.24 were determined with the test item at concentrations of 2, 5, and 10% (w/w) in propylene glycol, respectively. A statistically significant and biologically relevant increase in DPM value and also in lymph node

weight and cell count was not observed in any dose group in comparison to the vehicle control group. Furthermore, the cut-off value of 1.55 for a positive response regarding the lymph node cell count index reported for BALB/c mice was not reached in any dose group.

A general read-across justification with data matrices and structures has been added to the Chemical safety report (toxicokinetic section.)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for skin sensitization under Regulation (EC) No. 1272/2008, as amended for the fifthteenth time in Directive EC2020/1182.