Registration Dossier

Diss Factsheets

Administrative data

Description of key information

- Skin corrosion: Not corrosive based on read-across from Musk T which was tested in an OECD TG 404 test following GLP.

- Skin irritation: Not irritating based on read-across from Musk T which was tested in an OECD TG 404 test following GLP.

- Eye irritation: Not irritating based on read-across from Habanolide which was tested in an OECD TG 405 test following GLP.

- Respiratory irritation: not irritating (based on the non-irritant properties of skin and eyes)

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

For Zenolide, skin and eye irritating properties are derived from the close structural analogue Musk T and Habanolide, respectively. The summaries of the experimental information is presented first and thereafter the read across rationale.

Skin irritation

Key study with Musk T: The primary skin irritant effect of Musk T was investigated in a study performed in accordance with GLP and OECD TG 404. Four albino rabbits were exposed semi-occlusive to 5 different concentrations (100, 20, 10, 5, and 1% w/w) of the test substance at 6 skin sites on the back. After 4 hours of exposure the test article was removed, and the skin was examined 1, 24, 48 and 72 hours after termination of exposure. Slight dose related (100%, 20% and 10% test concentrations) skin erythema was observed 1 hour after termination of exposure. Thereafter, no abnormalities were observed. The substance is not considered a skin irritant under the experimental conditions.

Supporting Habanolide information: In the ECHA disseminated dossier of Habanolide, an OECD TG 404 study is presented showing that Habanolide is not a skin irritant.

Eye irritation

Key study with Habanolide: In an eye irritation study performed according to OECD guideline 405 and following GLP, 0.1 ml Habanolide was instilled into one eye of each of four rabbits. The animals were then observed for seven days. One hour after dosing, conjunctival discharge and hyperaemia were apparent in the treated eye of all 4 animals. In addition, conjunctival chemosis was noted in one rabbit. Twenty-four hours after dosing, these signs of irritation were no longer apparent and the eyes of all 4 rabbits appeared normal at the 48 and 72 hour observation periods. The substance is not considered an eye irritant based on these effects.

Supporting Musk T information: In the ECHA disseminated dossier of MuskT, an OECD TG 437 study is available showing that Musk T is not an ocular corrosive or severe irritant. In addition, an OECD TG 405 study is available showing that Musk T is not an eye irritant.

Respiratory irritation

For respiratory irritation mostly human data are used for the assessment because no suitable in vitro or in vivo tests are available that can identify respiratory irritation (ECHA guidance, 2017, page 240). There are no human data available that indicate respiratory reactions of the substance e.g. from consumer experience or occupational exposure. In addition, the substance is not corrosive or severely irritating and therefore respiratory irritation is not considered a concern.

Zenolide(CAS #54982-83-1) and its skin and eye irritation properties using read across from Musk T (CAS #105-95-3) and Habanolide (CAS #111879-80-2)

Introduction and hypothesis for the analogue approach

Zenolide is a cyclic aliphatic double ester. For this substance no skin and eye irritation information is available.In accordance with Article 13 of REACH, lacking information can be generated by means other than experimental testing, i.e. applying alternative methods such as QSARs, grouping and read-across.For assessing the irritation of Zenolide the analogue approach is applied. For the structural related analogues Musk T and Habanolide skin and eye irritation information is available, which can be used for read across to Zenolide.

Hypothesis: Zenolide is not a skin and eye irritant based on absence of irritant effects of Musk T and Habanolide.

Available information: Musk T is not a skin irritant in an OECD TG 404 study. Habanolide is not an eye irritant in an OECD TG 405 study. Both studies are performed following GLP and considered to be Klimisch 1. In addition, the ECHA disseminated dossiers of both structural analogues also show that Musk T is not an eye irritant and Habanolide is not a skin irritant.

Target chemical and source chemical(s)

The information on Zenolide, Musk T, and Habanolide supporting the read across are presented in the Data matrix.

Purity / Impurities

Zenolide is a mono-constituent with a high purity> 95% and therefore the impurities are not expected to influence the results.

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, which is presented below.

Analogue justification: Musk T is a very closely related structural analogue for which skin irritation information is available and therefore it is selected for justifying the read across. Habanolide is selected for eye irritation as such information was not available for Musk T in 2010, when Zenolide was REACH registered, and Habanolide is considered the next close analogue for Zenolide. On the ECHA dissemination site information is available on the eye irritation of Musk T and the substance is also not eye an irritant.

Structural similarities and differences: Zenolide and Musk T are that both are cyclic aliphatic di-esters. They have a similar backbone and similar functional groups. The difference between these two structures is that the cyclic alkyl chain of Musk T is one methyl group longer, which influence is discussed below. Zenolide and Habanolide also have similar backbones, which is a cyclic aliphatic alkyl chain, and both have an ester. The structural differences are that the aliphatic chain of Zenolide is fully saturated, while Habanolide has one double bond in this chain and Zenolide has two adjacent ester bonds, while Habanolide has one ester group. The influence of these differences on their irritating properties is discussed below.

Dermal absorption: Dermal absorption of Zenolide is expected to be similar to Musk T based on similarities in molecular weight, physical appearance and the physico-chemical properties.

Eye tissue absorption: Zenolide absorption is sufficiently similar to Habanolide. Zenolide has a higher molecular weight but a lower log Kow and higher water solubility, therefore the eye tissue absorption will be similar or slightly higher compared to Habanolide.

Skin irritation reactivity: The functional group of both Zenolide and Musk T is the double ester. Based on this, there is no difference in reactivity. The additional methyl group in Musk T does not affect this reactivity.

Eye irritation reactivity: The double ester of Zenolide double ester compared to the single ester of Habanolide is not expected to make a real difference in reactivity in view of the absence of adjacent electrophilic groups.

Uncertainty of the prediction: There are no remaining uncertainties, the absence of skin and eye irritation from Musk T and from Habanolide can be applied to Zenolide based on the above justification.The absence of skin and eye irritation presented on ECHA’s website on Habanolide and Musk T, respectively further support this information.

Data matrix

The relevant information on physico-chemical properties and other environmental fate properties are presented in the Data Matrix below.

Conclusions on skin and eye irritation

For Zenolide no information is available for skin and eye irritation, but this information is available for Musk T and Habanolide and this can be used for read across. When using read across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation. The current document fulfils this documentation. For the analogue Musk T, reliable skin irritation information is available (OECD TG 404, GLP, Klimisch 1) and for Habanolide a well conducted eye irritation test (OECD TG 405, GLP, Klimisch 1) is available, showing no irritant effects. In addition, the ECHA disseminated dossiers of Musk T and Habanolide show that Musk T and Habanolide are also not eye irritating and skin irritating, respectively. 

Final conclusion: Zenolide is not a skin or eye irritant.

 

Data matrix to support the read across to Zenolide from Musk T and Habanolide on skin and eye irritation

Common names

Zenolide

Musk T

Habanolide

Chemical structures

CAS no

54982-83-1

105-95-3

111879-80-2

34902-57-3

EC no

259-423-6

203-347-8

422-320-3

REACH Registered

Yes

Yes

Yes

Empirical formula

C14H24O4

C15H26O4

C15H26O2

Molecular weight

256

270

238

Phys-chem properties

 

 

 

Physical state

Liquid

Liquid

Liquid

Water solubility (mg/l)

75

14.8

0.95

Log Kow

3.65

4.3

5.45

Human health

 

 

 

Skin irritation

Not a skin irritant

(Read across)

Not a skin irritant

(OECD TG 404)

Not a skin irritant

(OECD TG 404)

(ECHA dissimination site)

Eye irritation

Not an eye irritant

(Read across)

Non-corrosive

(OECD 437)

Not an eye irritant

OECD TG 405)

(ECHA dissemination site)

Not an eye irritant

(OECD TG 405)

References:

Habanolide: ECHA disseminated dossier: https://echa.europa.eu/nl/registration-dossier/-/registered-dossier/5971

Musk T: ECHA disseminated dossier: https://echa.europa.eu/nl/registration-dossier/-/registered-dossier/14715

 

Justification for classification or non-classification

Based on the negative results of the available skin and eye irritation in vivo studies and the information available on respiratory irritation, classification of the substance for skin, eye, and respiratory irritation is not warranted according to EU CLP (EC 1272/2008 and its amendments).