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Description of key information

Skin sensitisation (OECD TG 429): sensitising; EC3 and NOEC are 3% and 1%, respectively.

HRIPT test at 6.25%: not sensitising.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Remarks:
Test has been performed before REACH regulation came into force requesting in vitro studies (October, 2016)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: read-across from a guideline study
Justification for type of information:
For assessing the skin sensitisation of Hexalon read across is used from Galbascone. The read across justification is presented in the Skin sensitisation Endpoint summary. The accompanying files are also attached there.
Reason / purpose for cross-reference:
read-across source
Parameter:
SI
Remarks on result:
other: The SI values calculated for the substance concentrations 0.1, 1, 10 and 100% were 0.9, 0.9, 10.4 and 17.5, respectively.
Key result
Parameter:
EC3
Remarks:
%
Value:
3
Parameter:
other: NOEC
Remarks:
%
Value:
1
Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Remarks:
according to EU CLP (1272/2008 and its updates)
Conclusions:
The substance is a skin sensitiser
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

A HRIPT study in which Hexalon is tested up to 6.25% is available for the substance itself. This information is considered insufficient to fulfil the REACH requirements. Therefore LLNA information from Galbascone (CAS# 56973 -85 -4) is used to read across to Hexalon. In this section first the first the LLNA of Galbascone is summarised, thereafter the HRIPT study with Hexalon and finally the full read across justification.

Galbascone skin sensitisation: LLNA

The skin sensitisation potential of the substance has been tested according to OECD TG 429: Local Lymph Node Assay" method (draft November 2000), non-GLP. At 0.1, 1, 10 and 100% the substance showed SI values of 0.9, 0.9, 10.4 and 17.5, respectively. Reliable negative and positive controls were included. No symptoms of local toxicity at the ears of the animals and no systemic findings were observed during the study period. These results show that the test substance could elicit a SI ≥ 3. An EC3 has been derived resulted in an EC3 of 3%. A NOEC of 1% is derived. Based on the results, the substance was considered to be a sensitiser and should be classified as skin sensitizer (Category 1B) and labeled as H317: May cause an allergic skin reaction According to Regulation (EC) No. 1272/2008.

Hexalon HRIPT

A HRIPT test was performed with 6.25% test substance in ethanol. 40 volunteers finished the study and were exposed to 1 mL solution mainly under semi-occlusive conditions. The subjects removed the bandages 24 hours after application. The basic schedule for this test is a series of nine 24-hour exposures on a Monday-Wednesday-Friday sequence for three successive weeks, the reaction to each exposure being scored at the session following and the reaction to the ninth application on Monday of the fourth week. The test patch was applied to the same site each time, unless reaction to sample or tape adhesive rendered this inadvisable, in which case the test patch was either omitted or applied to a fresh site. On Monday of the sixth week a challenge patch was applied to a site not previously exposed, and removed after 24 hours. Reactions to the challenge were scored on Wednesday and Friday of this week. Minor departures from this schedule were occasionally necessitated and were recorded. None of the 40 subjects tested was sensitized by the sample. Under the conditions of the test 6.25% test substance was not sensitising.

Assessing the sensitization potential of Hexalon (CAS:79-78-7) using Galbascone (CAS:56973-85-4)

Introduction and hypothesis for the analogue approach for skin sensitization

Hexalon (CAS #79-78-7) has a trimethyl-cyclohexene backbone with an alkyl chain to it. The alkyl chain has an alpha-beta conjugated ketone bond and has an allyl bond at the end of the chain.

In accordance with Article 13 of REACH, lacking information can be generated by applying alternative methods such asin vitrotests, QSARs, grouping and read-across. In this case read across will be used for assessing the skin sensitising potential of Hexalon using Galbascone as an analogue. This analogue has a similar molecular structure compared to Hexalon and therefore information from Galbascone can be used to determine the skin sensitising potential of Hexalon (see data matrix).

Hypothesis:Hexalon (target) has similar sensitization potential compared to Galbascone (source) resulting in a similar skin sensitising effect because both molecular structures are similar.

Available information:For Hexalon aHRIPT test with 6.25% substance is available. In this study no skin sensitisation was observed, however the endpoint requirements cannot be fulfilled with this information. For the analogue Galbascone a Local Lymph Node Assay is available which result can be used for Hexalon. The assay was performed according to OECD TG 429: Local Lymph Node Assay method. The study was assigned reliability 1.

2. Target chemical and source chemical(s)

Chemical structures of the target and the source are shown in the data matrix (see also the attached document in IUCLID section 7.4).

3. Purity / Impurities

Hexalon contains one main constituent present at ca. 78%, a constituent present at ca. 10% and three additional constituents all present below 5%. Except one (1.3%) all minor constituents of Hexalon have similar structures: a ring with an alkyl chain with a ketone group. This minor one has more a ring type of structure instead of a chain which is not expected to have a more severe skin sensitisation potential compared to the other constituents. Galbascone contains two constituents that are isomers.As a result it is not expected that the impurities of the source and target chemicals affect the read-across justification.

4. Analogue approach justification

According to Annex XI 1.5 read across can be used to replace testing when the similarity can be based on a common backbone and “a common functional group”. When using read across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation. This read across will be based on a common structural backbone and common functional groups. The ECHA guidance (2015, RAAF) has been used as a guide.

Structural similarities and differences:Hexalon has a trimethyl-cyclohexene backbone with an alkyl chain attached to it. The functional group is the alpha-beta conjugated ketone group which is expected to cause skin sensitisation. At the end of the alkyl chain there is an allyl bond which is not considered to be very reactive as such. Galbascone has a somewhat similar backbone, similar functional group and also an allyl group at the end of the alkyl chain. The difference is that Hexalon has this alpha-beta conjugated bond just outside the ring while Galbascone has it inside the ring. This is expected not to influence the skin sensitisation reactivity because both functional groups are slightly hindered by the ring structure: Galbascone having the group in the ring and Hexalon has this group just outside the ring.

Toxico-kinetic similarities and differences:For skin sensitisation the dermal absorption is of secondary importance. Galbascone is expected to have a higher dermal absorption because of its lower log Kow 4.5 versus 5.5 of Hexalon.Based on this Galbascone may have a slightly higher the sensitisation potential.

Metabolism: For Hexalon (and Galbascone) the parent substance is expected to present the highest sensitisation potential because of the alpha-beta conjugated bond (Michael addition reactivity). Therefore the metabolites are not further considered here.

Toxico-dynamic aspect such as Reactivity:Hexalon and Galbascone have a Michael addition reactivity based on their alpha-beta conjugated ketone group (OECD Toolbox). The reactivity depends on the susceptibility of the molecular site where the protein will be covalently bound to the substance, which is on the alkyl side of the double bond. The alpha-beta conjugation in the ring possibly slightly diminishes this reactivity. Hexalon has the alpha-beta conjugation outside the ring. The double bond is only one methyl group away from the ring. The ring actually may somewhat sterically hinder the protein attack at the double bond position (based on Michael addition). Therefore reactivity of Hexalon and Galbascone considered similar.

Experimental data similarity and difference:The skin and eye irritation endpoints are other local endpoints for which reactivity is a key parameter. Both substances are not skin and eye irritants supporting the similarity in reactivity.

Uncertainty of the prediction:There is no remaining uncertainty, in view of similarities in structure, and reactivity, as presented above the read across is justified.

5. Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the Data matrix in Table 1.

6. Conclusions per endpoint for hazard, C&L and dose descriptor

For Hexalon only HRIPT sensitisation study is available. Therefore additional information regarding the skin sensitisation potential of Hexalon is needed. For an analogue, Galbascone, the LLNA (OECD TG 429) resulted in an EC3 of 3% and a NOEC of 1%. Using the information from Galbascone for Hexalon it can be concluded that Hexalon is a skin sensitiser category 1B. The NOEC of 1% will be the starting dose descriptor for the risk characterisation.

Final conclusion on hazard, C&L, DNEL and risk characterization

The substance is a skin sensitiser. According to EU CLP (No. 1272/2008 and its amendments) the substance is classified as a skin sensitizer category 1B. For the risk characterisation the NOEC of 1% will be used as the starting dose descriptor.

Data matrix for assessing the skin sensitisation of Hexalon using read across from Galbascone

Common name

Hexalon

Galbascone

Chemical structures*,

Chemical name

1-(2,6,6-Trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one

1-(5,5-dimethyl-1-cyclohexen-1-yl)pent-4-en-1-one

CAS no

79-78-7

56973-85-4

Einecs

201-225-9

260-486-7

REACH registration

Registration for 2018

Registration for 2018

 

201-225-0

260-486-7

Smiles

O=C(C=CC(C(=CCC1)C)C1(C)C)CCC=C

CC1(C)CC(=CCC1)C(=O)CCC=C

Molecular weight

232

192

Appearance

Liquid

Liquid

Physico-chemical data

 

 

Melting point, °C

-20

-20

Vapour pressure, Pa

0.08

1.14

Water solubility, mg/l

79

89

Log Kow

5.5

4.5

Human health

 

 

Skin irritation/corrosion

not irritating (OECD 439)

not irritating (OECD 404)

Eye irritation/corrosion

not irritating (OECD 438)

not irritating (OECD 405)

Skin sensitisation

HRIPT: 6.25% no sensitisation

EC3 derived by read across

Skin sensitizer Category 1B (OECD 429)EC3 of 3%. A NOEC of 1%

 

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The substance is not a skin sensitiser because there are no human data that indicate respiratory skin sensitisation. In addition the potential for respiratory sensitization of the substance is assessed using the integrated evaluation strategy for respiratory sensitization data in the ECHA guidance (R7A, Fig. 7.3-2).

1)           The substance is a moderate skin sensitizer;

2)           The substance does not belong to the di-isocyanates;

3)           The substance has not structural alerts or is structurally related to chemicals causing respiratory sensitization as presented in Table R.7.3-1 in the ECHA guidance of 2008 or those provided in the following document: http://ec.europa.eu/health/scientific_committees/docs/annex6_respiratory.pdf

Using this ITS in the ECHA guidance it can be concluded that Hexalon is not a respiratory sensitiser.

Justification for classification or non-classification

The substance needs to be classified as a skin sensitiser category 1B (H317) according to EU CLP (Regulation (EC) No. 1272/2008 and its updates). When using the testing strategy for respiratory sensitisation the substance does not need to be classified and labelled in accordance with EU CLP (Regulation (EC) No. 1272/2008 and its updates).

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