Pentadecan-15-olide

Endpoint summary

Description of key information

Pentadecan-15-olide is bioavailable via oral route. Limited systemic absorption via inhalation and dermal route is anticipated. The substance will cross cellular barriers or will be distributed into fatty tissues. Pentadecan-15-olide is expected to undergo hydrolysis and to be mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

There is no specific requirement to generate toxicokinetic information in REACH. Therefore, the toxicokinetic profile of pentadecan-15-olide (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information. The physical chemical characteristics of the substance, the results obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays were used to predict the toxicokinetic behavior of pentadecan-15-olide.

Physico chemical properties:

Pentadecan-15-olide is a mono-constituent substance having a relatively low molecular weight of 240.38 g/mol. The substance is slightly water soluble (0.3 mg/L), highly lipophilic based on the octanol/water partition coefficient (log Kow = 5.78) and not volatile according to its vapour pressure (0.085 Pa at ambient temperature).

Absorption:

The physical chemical characteristics described above suggest that pentadecan-15-olide is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being lipophilic, pentadecan-15-olide may be expected to cross gastrointestinal epithelial barriers even if the absorption may be limited by the inability of the substance to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface. Moreover, the absorption will be enhanced if pentadecan-15-olide undergoes micellular solubilisation by bile salts. Substances absorbed as micelles will enter the circulation via the lymphatic system, bypassing the liver.

Acute oral gavage toxicity studies conducted on pentadecan-15-olide and on the supporting substance (EC 422 -320 -3, refer to Section 13 for read-across justification) identified neither mortality nor clinical signs (LD50 > 2000 mg/kg bw). However macroscopic findings, such as swollen and/or darkened liver and mottled renal cortex were observed in one study. A 90-day repeated dose study, a pre-natal/developmental toxicity study and a one-generation reproduction toxicity study conducted on the supporting substance (EC 422 -320 -3) using the oral route (gavage) gave a NOAEL ≥ 1000 mg/kg bw/day. No treatment-related effects were observed in these two studies. The lack of significant adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material and/or its metabolites, or to a very low inherent toxicity of pentadecan-15-olide. However, the observation of systemic effects, even if of very low toxicological concern, indicates the oral bioavailability of pentadecan-15-olide and/or its metabolites.

Regarding the dermal absorption, pentadecan-15-olide being lipophilic (log Kow = 5.79), the rate of uptake into the stratum corneum is expected to be high while the rate of penetration is likely to be limited by the rate of transfer between the stratum corneum and the epidermis. Moreover, it is assumed that the dermal uptake is also limited by the slight water solubility of pentadecan-15-olide. Pentadecan-15-olide has been identified as a skin sensitizer, some uptake must have occurred although it may only have been a small fraction of the applied dose. These assumptions are supported by the absence of systemic effects following single-dose dermal application of up to 5000 mg/kg bw pentadecan-15-olide or the supporting substance (EC 422 -320 -3), which would suggest a limited systemic absorption through cutaneous barriers. Moreover, enhanced skin penetration is not expected since pentadecan-15-olide is not a skin irritant or corrosive.

The potential for inhalation toxicity was not evaluated in vivo. However, the vapour pressure of pentadecan-15-olide (0.085 at ambient temperature) indicated an absence of volatility and therefore no exposure by inhalation is anticipated. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance

Distribution

Systemic distribution of pentadecan-15-olide can be predicted from its physical chemical characteristics. Considering that the substance is highly lipophilic (log Pow >4) and slightly water soluble, it is suggested that, upon systemic absorption, pentadecan-15-olide may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. Afterwards, based on its lipophilic character, the substance will readily cross cellular barriers or will be distributed into fatty tissues with a low potential to accumulate.

Metabolism:

Pentadecan-15-olide is expected to undergo hydrolysis to its corresponding alcohol and acid.

Excretion:

Pentadecan-15-olide having a molecular weight lower than 300, it is expected to be mainly excreted in urine and no more than 5-10% may be excreted in bile. Any substance that is not absorbed from the gastro-intestinal tract, following oral ingestion, will be excreted in the faeces. Following dermal exposure, highly lipophilic substances, such as pentadecan-15-olide, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.