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No toxicokinetic studies on delta-damascone were available. Therefore, the assessment of its toxicokinetic behaviour was based on the general description of the whole group of ionones and damascones presented in Belsito et al. (2007), which is described below.

 

Structural considerations (after Belsito et al., 2007)

The group of ionones can be divided into two major groups – ionones and rose ketones, with one compound common to both groups (1-(2,6,6-trimethyl-1-cyclohexen-1-yl)butane-1,3-dione) (Belsito et al., 2007).

Rose ketones have been defined as fragrance ingredients with the general formula 1-(trimethylcyclohexenyl/hexadienyl)-2-buten-1-one. The cyclohexenyl derivates are called damascones, and the cyclohexadienyl derivatives are called damascenones.

 

As such, delta-damascone falls in the category of damascones, while its structural analogue alpha-iso-methylionone falls in the group of ionones. Delta-damascone and alpha-isomethylionone are structural homologues of each other, since both have a cyclohexenyl ring with three methyl groups on the 2,6,6 positions, attached to an allylic side chain containing a ketone moiety. The allylic side chain of delta-damascone is a 2-buten-1-one group and of alpha-iso-methylionone a 3-buten-2-one group. Both are alpha-beta unsaturated ketones. Delta-damascone may exhibit some higher reactivity based on structural grounds, because it does not have the methyl group attached to alpha-beta unsaturated ketone, which is expected to somewhat hinder the reactivity. The differences between the allylic side chains in the two substances are the switched positions of the allylic double bond and the ketone.

 

The structures of 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)butane-1,3-dione, delta-damascone and its structural analogue analogue alpha-iso-methylionone are shown in the attached document.

Physico-chemical properties (after Belsito et al., 2007)

The physico-chemical properties of delta-damascone and alpha-isomethylionone are similar, with both substances having similar water solubility (77.2 mg/L (Huntingdon Life Sciences Ltd., 2008b) and 16 mg/L (Test Plan for ionone derivatives, submitted to EPA, 2002), respectively) and vapour pressure (2.72 Pa at 23°C(International Flavors & Fragrances Inc., 2009b)and 1.5 Pa (calculated; Test Plan for ionone derivatives, submitted to EPA, 2002), respectively). The substances have log Kow of 4.2 and 4.7, respectively, which illustrates that they are highly lipophilic.

 

No physico-chemical properties of other rose ketones and ionones are present in this dossier. However, in view of their structural similarities, it can be anticipated that the physico-chemical properties such as vapour pressure, water solubility and partition coefficient may also be comparable (Belsito et al., 2007).

 

Absorption and toxicokinetic information from systemic toxicity endpoints (after Belsito et al., 2007)

No specific data are available on the dermal absorption of ionones and/or rose ketones. However, based on data on fragrance ketones and aldehydes for which in vivo absorption data are available, it can be anticipated that dermal absorption of ionones/rose ketones is likely to be significant. There also are no oral pharmacokinetic studies available from which the bioavailability of this class of compounds can be quantitatively determined. However, based on metabolic studies on ionones in which metabolites were recovered in the urine of rabbits and dogs treated orally, oral absorption of these compounds does occur to some extent (Belsito et al., 2007). Additionally, mortality was seen in the acute oral toxicity study with delta-damascone, and sensitisation was observed in the skin sensitization study with delta-damascone. Furthermore, systemic toxicity was seen in the 90-day oral toxicity study with alpha-iso-methylionone. These observations indicate that the substance can be absorbed via both the oral and dermal route.

 

No data on inhalation absorption were available. Considering the fact that ionones and rose ketones are absorbed via both the oral and dermal route to some extent, it can be anticipated that also inhalation absorption may occur.

 

Metabolism (after Belsito et al., 2007)

Ionones and rose ketones, because of their highly lipophilic nature, would be expected to be extensively metabolized in vivo and eliminated as transformation products (Belsito et al., 2007). This indeed was observed in several studies involving the administration of alpha-and beta-ionone to rabbits and dogs. Little unchanged compound was recovered from the urine compared to the relatively large amounts of transformation products that could be isolated. Based on the molecular structures of the ionones and rose ketones several metabolic options might be predicted (Belsito et al., 2007):

-         1. hydroxylation/oxygenation of the cyclohexene ring;

-         2. reduction of the buteneone group to a secondary alcohol;

-         3. oxidation of the substituting methyl groups;

-         4. reduction of the double bond in the exocyclic alkenyl side chain to form dihydro derivatives;

-         5. conjugation of the hydroxylated metabolites with glucuronic acid;

-         6. conjugation with glutathione

 

The most complete in vivo metabolic data are from animal studies; there are no human data available for these compounds. The most extensive data are for beta-ionone with a limited amount of data for the alpha isomer; the metabolic data available can be viewed as being representative for the class as a whole. Following administration of beta-ionone to a male rabbit (oral gavage, 1 g/day for seven days), the following transformation products were isolated and characterised: 3-oxo-beta-ionone, 3-oxo-beta-ionol, dihydro-3-oxo-beta-ionol and 3-hydroxy-beta-ionol together with the glucuronides of 3-oxo-beta-ionol and dihydro-3-oxo-beta-ionol. Only a small amount of unchanged beta-ionone (circa 1% of dose) was recovered from the urine of the dosed animal.

 

In an earlier study, beta-ionol and dihydro-beta-ionol were isolated as reduction products from the urine of dogs fed beta-ionone; three additional hydroxylated metabolites were detected but not characterised. These findings were confirmed in another study, which identified 3-oxo-beta-ionol and 3-hydroxy-beta-ionol or 3-hydroxy-beta-ionone. In a single metabolic study of alpha-ionone in mammals, a transformation product in urine of rabbits was isolated which appeared to be an oxidation product, tentatively identified as 4-oxo-tetrahydro-ionone (Belsito et al., 2007).

 

The metabolisation pathways of delta-damascone and alpha-iso-methylionone are also expected to be similar (Belsito et al., 2007). Several metabolic pathways can be envisaged, i.e. hydroxylation/oxygenation of the cyclohexene ring (the cyclohexene ring as such is not sufficiently electronegative to form an epoxide), the reduction to the buteneone group to a secondary alcohol, oxidation of the angular methyl groups, reduction of the double bond in the exocyclic alkenyl side chain to form dihydro derivatives and conjugation with glutathione (see metabolic prediction on general ionones, described above).

 

In summary, the available evidence indicates that the ionones and rose ketones are extensively metabolised in vivo by pathways involving oxidation, reduction and conjugation.

 

Summary (after Belsito et al., 2007)

In summary, the available evidence indicates that absorption of delta-damascone after oral, dermal and inhalation exposure is significant and after absorption in vivo extensive metabolism occurs by pathways involving oxidation, reduction and conjugation. No quantitative measures could be derived for oral, dermal and inhalation absorption. Therefore, in the current risk assessment performed under REACH, the default factors for route-to-route extrapolation, as suggested in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment, were used (see DNEL section).

 

The metabolites formed did not raise issues of toxicological concern (Belsito et al., 2007).