2,20:3,19-Dimethano-2,3,4a,5a,6a,7a,8a,9a,10a,11a, 12a,13a,14a,15a,16a,17a,19 ,20,21a,22a,23a,24a,25a,26a,27a,28a,29a,30a,31a,32a,33a,34a-dotriacontaazabispentaleno [1''',6''':5'',6'',7''] cycloocta[1'',2'',3'':3'',4'']pentaleno[1'',6'':5',6',7']cycloocta[1',2',3':3',4']pentaleno[1',6':5,6,7]cycloocta[1,2,3-gh:1',2',3'-g'h']cycloocta[1,2,3-cd:5,6,7-c'd']dipentalene-1,4,6,8,10,12,14,16,18,21,23,25,27,29,31,33-hexadecone, hexadecahydro-, stereoisomer,2,18:3,17-Dimethano-2,3, ,4a,5a,6a,7a,8a,9a,10a,11a,12a,13a,14a,15a,17,18,19a, 20a,21a,22a,23a,24a, 25a,26a,27a,28a,29a,30a-octacosaazabispentaleno[1''',6''':5'',6'',7'']cycloocta [1'',2'',3'':3'',4''] pentaleno[1'',6'':5',6',7']cycloocta[1',2',3':3',4']pentaleno[1',6':5,6,7]cycloocta[1,2,3-cd:1',2',3'-gh]pentalene-1,4,6,8,10,12,14,16,19,21,23,25,27,29-tetradecone, tetradecahydro-, stereoisomer, 1H,4H,12H,15H-2,14:3,13-Dimethano-5H,6H,7H,8H,9H,10H,11H,16H,17H,18H,19H,20H,21H,22H-2,3,4a,5a,6a,7a,8a,9a,10a,11a,13,14,15a,16a,17a,18a,19a,20a,21a,22a-eicosaazabispentaleno [1'',6'':5',6',7']cycloocta[1',2',3':3',4']pentaleno[1',6':5,6,7]cycloocta[1,2,3-cd:1',2',3'-gh]pentalene-1,4,6,8,10,12,15,17,19,21-decone, decahydro-, stereoisomer

Endpoint summary

Description of key information

The substance was found to be a non-sensitiser in chemico (direct peptide reactivity assay according to OECD test guideline 442C, GLP study). Applying the integrated approach recommended in the OECD IATA guideline on skin sensitisation, this result was combined with other complementary information in a Weight-of-Evidence approach. As a result, there was sufficient evidence to conclude on the absence of sensitising properties of this multi-constituent substance (“reaction mass of cucurbit[6]uril, cucurbit[7]uril and cucurbit[8]uril”). This conclusion is based on read-across information from cucurbit[8]uril hydrochloride hydrate, together with other supporting evidence. The analogue substance cucurbit[8]uril hydrochloride hydrate was not a skin sensitiser in a GLP guideline study according to OECD TG 429. The analogue substance has a similar structure containing identical monomer units and functional groups, has a similar toxicity profile and similar physico-chemical properties (cf. data matrix). In addition, the following lines of evidence support the read-across:

-     the physico-chemical properties of “reaction mass of cucurbit[6]uril, cucurbit[7]uril and cucurbit[8]uril” suggest a lack of penetration into viable epidermis;

-     the lack of structural alerts and the prediction of “non-sensitiser” with the VEGA CAESAR QSAR model, 2018 version);

-     the lack of protein reactivity in the OECD 442C assay;

-     the lack of activity in in vitro skin irritation and genotoxicity assays; and

-     the lack of formaldehyde release in artificial sweat experiments.

Given that none of several different lines of evidence gives any indication of a sensitising potential, the overall confidence level in the assessment is high. The adaptation of information requirements (here: a battery of in vitro sensitisation tests) according to Annex XI (REACH) provisions (based on weight of evidence, including read-across) is therefore considered adequate.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in chemico

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

25 May 2018 to 06 June 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 442C (In Chemico Skin Sensitisation: Direct Peptide Reactivity Assay (DPRA))

Version / remarks:

2015

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of study:

direct peptide reactivity assay (DPRA)

Details on the study design:

The study was performed according the OECD guideline 442C to quantify the remaining concentration of cysteine- or lysine-containing peptide following at least 22 hours incubation with the test material at 25 +/- 2.5ºC. Relative peptide concentration was measured by HPLC with gradient elution and UV detection at 220 nm. Cysteine and lysine peptide percent depletion values were calculated.

Key result

Parameter:

other: % cysteine depletion

Value:

0.068

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Remarks on result:

no indication of skin sensitisation

Key result

Parameter:

other: % lysine depletion

Value:

0.329

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Remarks on result:

no indication of skin sensitisation

Interpretation of results:

study cannot be used for classification

Conclusions:

The test item was successfully analysed by the validated DPRA analytical method in both Cysteine and Lysine containing synthetic peptides. With minimal mean depletion of both peptides in the presence of the test item (0.0680% cysteine depletion; 0.329% lysin depletion). The test material is therefore predicted by DPRA as negative and not to be a potential skin sensitizer based on this assay.

Executive summary:

A GLP in chemico study was performed following the method described in the OECD test guideline 442C (direct peptide reactivity assay (DPRA)). No depletion was found after incubation of the peptides with the test material for 22 hours at 25°C.

Reference 2

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source and target substances are structurally very similar with both consisting of the same monomeric units forming macrocylic compounds containing 6, 7 or 8 units (target substance) or 8 units (source substance). The functional groups are therefore identical. Source and target substance have similar physico-chemical properties and available toxicity data have revealed a very similar toxicity profile. Although not all starting materials
for the synthesis are identical, the breakdown products - as far as known - do not differ. Both source and target form host guest complexes by a common meachanism of action. Therefore, read-across is justified.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source substance is the hydrochloride hydrate of one of the constituents of the target substance. Neither source nor target substance contain toxicologically relevant impurities in relevant amounts.
3. ANALOGUE APPROACH JUSTIFICATION
All experimental data available to date are very similar for source and target substance and confirm the analogue approach.

Reason / purpose for cross-reference:

read-across source

Guideline:

EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)

GLP compliance:

yes (incl. QA statement)

Type of study:

mouse local lymph node assay (LLNA)

Key result

Parameter:

SI

Value:

1

Test group / Remarks:

25%

Key result

Parameter:

SI

Value:

1.3

Test group / Remarks:

10%

Key result

Parameter:

SI

Value:

1.1

Test group / Remarks:

5%

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The substance does not Meet the EU and GHS criteria for skin sensitisation classification.