Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

Based on the presence toxicity studies, physico-chemical parameters, and modelled data, Delta-damascone is expected to be readily absorbed via the oral and inhalation route and lower via the dermal route. The final absorption percentages derived are: 50% oral absorption, 10% dermal absorption and 100% inhalation absorption.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

Toxicokinetics: Absorption, Distribution, Metabolism and Excretion


Introduction


Delta-damascone (Cas no 57378-68-4) has a cyclohexenyl ring with three methyl groups on the 2,6,6 positions, attached to an allylic side chain containing a conjugated ketone moiety. The allylic side chain of delta-damascone is a 2-buten-1-one group. Delta-damascone is a colourless to pale yellow liquid with a molecular weight of 192.3 g/mol that does not preclude absorption. The substance has a low volatility (vapour pressure 2.7 Pa).


Absorption


Oral: The adverse effects of the oral repeated dose toxicity study of the analogue Alpha-iso-methylionone shows that it is being absorbed by the gastro-intestinal tract following oral administration. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 4.2) and water solubility (77.2 mg/l) would favour absorption through the gut. According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. In addition the substance is mainly a hydrocarbon with only one oxygen atom in its molecule, which can act as a single hydrogen acceptor. This indicates high oral absorption (98%) when using the Zhao et. al (2003) equation:


% oral absorption = 100 x [1-Exp(-100.747-340A-0.155B)] = 100 x [1-Exp(-3.91)]


In this equation A is the hydrogen bond donor and B the hydrogen bond acceptor. For Delta-damascone the value for A is zero because there is no atom that can be a hydrogen bond donor. For B the result is one because the oxygen atom can be a hydrogen acceptor.


Though this equation has been established for drugs it is expected to be also an indicator for oral absorption of other substances with somewhat similar physico-chemical properties. In summary, it can be anticipated that the oral absorption will be much higher than 50% and likely to be close to 100% but for the risk assessment the default value of 50% will be used.


Skin: The optimal MW and log Kow for dermal absorption is <100 g/mol and in the range of 1-4, respectively (ECHA guidance, R7C, Table R.7.12-3). Based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (192.3 g/mol), log Kow (4.2) and water solubility (77 mg/l) it can be anticipated that some dermal absorption is likely. The substance is a skin irritant and skin sensitizer, which indicates that the substance passes the stratum corneum. An in vitro study on Methylionone (1335-46-2) showed 50% dermal absorption in rat but only 0.7% could be retrieved in the receptor fluid, indicating low systemic exposure via the dermal route (Belsito et al., 2007). For Alpha-damascone (24720-09-0) the dermal absorption was considered to be close to 50% (Ten Berge, 2010 and Kasting and Saiyasombati, 2001) but this value seems to be derived based on an evaporation model rather than actual absorption information and therefore this information is disregarded. It can be concluded that delta-damascone is outside the optimal range for dermal systemic absorption and because a similar substance showing < 1% systemic availability, the dermal absorption will not exceed 10%.


Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure route is thought minor, because of its low volatility (2.7 Pa), the octanol/water partition coefficient (4.2), indicates that inhalation absorption is possible. The blood/air (BA) partition coefficient is another partition coefficient indicating lung absorption. Buist et al. (2012) have developed BA model for humans using the most important and readily available parameters:


Log PBA = 6.96 – 1.04 Log (VP) – 0.533 (Log) Kow – 0.00495 MW.


For Delta-damascone the BA partition coefficient would be 6.96 – 1.04 x 0.43 – 0.533 x 4.2 – 0.00495 x 192.3 = 3.3


This means that Delta-damascone has a tendency to go from air into the blood. It should, however, be noted that this regression line is only valid for substances which have a vapour pressure > 100 Pa. Despite the substance being somewhat out of the applicability domain and the exact BA may not be fully correct, it can be seen that the substance will be readily absorbed via the inhalation route and will be close to 100%.


Distribution


The moderate water solubility (77 mg/L) of the substance would limit distribution in the body via the water channels. The log Kow (4.2) would suggest that the substance would pass through the biological cell membrane. Due to the expected metabolisation the substance as such would not accumulate in the body fat which is confirmed in the bioaccumulation study in fish, which showed a BCF of 58.


Metabolism


There are no actual data on the metabolisation of Delta-damascone. Several possible 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), reduction to the butenone 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 (WHO, 1999). The metabolites formed did not raise issues of toxicological concern (Belsito et al., 2007). In the read across documentation presented also in this section an overview of the metabolisation scheme is presented as well as metabolites according to the OECD Toolbox rat metabolism simulator.


Excretion


In view of the anticipated water solubilities of the metabolites the primary route of excretion will be through the urine. Any unabsorbed substance will be excreted via the faeces.


Discussion


Delta-damascone is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters. The substance also is expected to be absorbed dermally to some extent based on the physico-chemical properties though the MW and the log Kow are outside the favourable range. For methylionone the dermal absorption for systemic exposure was < 1% and for Delta-Damascone a similar value can be anticipated (Belsito et al., 2007). This low dermal absorption is further supported with the observed skin irritant and sensitizing properties. This means that absorption through the stratum corneum is likely but in view of this reactivity the dermal systemic absorption is considered to be limited and is considered to be lower than 10%.


Oral to dermal extrapolation: There are adequate data via the oral route and the critical toxic effect is related to systemic effects and therefore route to route extrapolation is applicable. The toxicity of the substance will be due to the parent compound but also to its metabolites. The overriding principle will be used to avoid situations where the extrapolation of data would underestimate toxicity resulting from human exposure to a chemical by the route to route extrapolation. Delta-damascone is expected to be absorbed to high extent via the oral route in view of its physico-chemical properties and structural properties but the default value of 50% will be used. Some first pass effect via the liver is expected to occur. The systemic dose via the dermal route is expected to be lower than the oral route in view of the physico-chemical properties, the dermal reactivity and supporting information on the systemic dermal absorption of Methylionone. Therefore it will be assumed that the oral absorption will exceeds dermal absorption with a factor of 5. This factor still includes the asymmetric handling of uncertainty. The oral absorption will be considered 50% and the dermal absorption will be considered 10%.


Oral to inhalation extrapolation: Though Delta-damascone is not a volatile liquid some inhalation exposure may occur. Delta-damascone is not expected to be a respiratory irritant and therefore systemic effect will overrule the effects at the site of contact. The overriding principle will be used to avoid situations where the extrapolation of data would underestimate toxicity resulting from human exposure to a chemical by the route to route extrapolation and therefore 50% oral absorption and 100% absorption will be used for route to route extrapolation.


Conclusion


Delta-damascone is expected to be readily absorbed via the oral and inhalation route and lower via the dermal route based on toxicity, physico-chemical and modelled data. The final absorption percentages derived are: 50% oral absorption, 10% dermal absorption and 100% inhalation absorption.


References


Belsito D, Bickers D, Bruze M, Calow P, Greim H, Hanifin JM, Rogers AE, Saurat JH, Sipes IG, Tagami H., 2007, A toxicologic and dermatologic assessment of ionones when used as fragrance ingredients. Food Chem Toxicol. 2007;45 Suppl 1:S130-67.


Buist, H.E., Wit-Bos­ de, L., Bouwman, T., Vaes, W.H.J., 2012, Predicting blood:air partion coefficient using basis physico-chemical properties, Regul. Toxicol. Pharmacol., 62, 23-28.


Kasting, G.B and Saiyasombati, P., 2000, A physico-chemical properties based model for estimating evaporation and absorption rates of perfumes from skin, Intern. J. Cosmetic Sci., 23, 49-58.


Martinez, M.N., And Amidon, G.L., 2002, Mechanistic approach to understanding the factors affecting drug absorption: a review of fundament, J. Clinical Pharmacol., 42, 620-643.


Ten Berge, W., Huizer, D., and Jongeneelen, F., 2010, Skin Absorption of (volatile) Liquids: A skin-PBPK Model, A CEFIC-LRI project PPP Conference 2010,http://www.cefic-lri.org/uploads/LRI%20Toolbox/IndusTox%20Poster.pdf


WHO, 1999, Ionones and structurally related substances, Safety Evaluation of certain food additives: 42,http://www.inchem.org/documents/jecfa/jecmono/v042je19.htm


Zhao, Y.H., Abraham, M.H., Hersy, A., Luscombe, C.N., 2003,Quantitative relationship between rat intestinal absorption and Abraham descriptors, Eur. J. Med. Chem., 38, 939-947.