2,2,5-trimethyl-5-pentylcyclopentan-1-one

Endpoint summary

Description of key information

The available evidence suggests that the substance is bioavailable via the oral, dermal and inhalation route. The substance is expected to be mainly excreted in urine. The substance has a potential to bioaccumulate.

Additional information

In accordance with the section 8.1.1 of Annex VIII of Regulation (EC) No 1907/2006 (REACH), the toxicokinetic profile of the substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information collated in the dossier. The physical chemical characteristics of the registered substance and supporting substances (see Section 13 for read-across justification), the results obtained from acute, repeated-dose, and reproductive toxicity studies, as well as information gained from genotoxicity assays were used to predict its toxicokinetic behaviour.

The JECFA assessment on Alicyclic ketones, secondary alcohols and related esters (JECFA, 2007) was also used to support this toxicokinetic assessment.

Physical-chemical properties:

The substance is a mono-constituent, having a relatively low molecular weight of 196.3 g/mol. The substance is a slightly water soluble liquid (18.9 mg/L) and is highly lipophilic based on the octanol/water partition coefficient (Log Kow = 4.7). The substance has low volatility according to its vapour pressure (9.2 Pa at 25°C).

Absorption:

Oral/GI absorption

The physical chemical characteristics described above suggest that the registered substance is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being lipophilic, the registered substance 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 the registered substance undergoes micellar solubilisation by bile salts. Substances absorbed as micelles will enter the circulation via the lymphatic system, bypassing the liver.

These hypothesis are supported by oral systemic effects, as summarized below:

- In an acute oral gavage toxicity study, signs of discomfort (e.g. hunched posture) were the only findings observed at high dose levels (≥ 3038 mg/kg bw; LD50 > 6834 mg/kg bw).

- The Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test gave a NOAEL of 12000 ppm (equivalent to 704 mg/kg bw/day in male rats and 683 mg/kg bw/day in female rats), based on the absence of significant effects that could be considered to be adverse up to the highest dose tested. However a clear adaptive effect on liver was observed in males and females (minimal hepatocellular hypertrophy and increased liver weight).

The observation of systemic effects even if limited indicates the oral bioavailability of the substance and/or its metabolites.

In light of these data, and the lack of specific information on any the registered substance or its supporting substances, the registered substance was assumed to be 100% bioavailable by oral route for the purpose of human health risk assessment.

Dermal absorption

Regarding dermal absorption, the registered substance being lipophilic, 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 the registered substance. Even if the registered substance is surface-active and may enhance penetration and therefore enhance the dermal uptake, the absence of systemic effects following single-dose dermal application of the substance at doses above 2000 mg/kg bw would suggest a limited systemic absorption through cutaneous barriers.

In light of these data, and the lack of specific information on any the registered substance or its supporting substances, a dermal absorption of 100% was conservatively assumed for the purposes of human health risk assessment.

Respiratory absorption

The potential for inhalation toxicity was not evaluated in vivo.

The vapour pressure of the substance (Vp = 9.2 Pa at 25°C) indicated a low volatility and inhalability and therefore no significant exposure by inhalation is anticipated. Thus, at ambient temperature, no significant respiratory absorption is expected under normal use and handling of the substance.

However, when used as a vapour in aerosol, the substance is expected to be directly absorbed across the respiratory tract epithelium by passive diffusion.

In light of these data, and the lack of specific information on respiratory absorption, the substance was conservatively assumed to be 100% bioavailable by inhalation for the purposes of human health risk assessment.

Distribution:

Systemic distribution of the registered substance 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, the registered substance 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 may readily cross cellular barriers or may be distributed into fatty tissues with a potential to accumulate. Due to its high lipophilic property, the substance could readily penetrate the stratum corneum but are not expected to be systemically absorbed to a major extent.

Metabolism:

Specific data on metabolism of the registered substance is not available. There is some evidence of enhanced metabolism following repeat oral exposure of substance in rats in the repeat dose toxicity studies. Metabolism did not influence genotoxicity in Ames test. In general, alicyclic ketones are reduced to the corresponding secondary alcohol and excreted primarily as glucuronic acid conjugates. Alicyclic ketones containing an alkyl side-chain can not only follow reductive pathways but can undergo oxidation of the side-chain to form poly-oxygenated metabolites, which are excreted as the glucuronic acid or sulphate conjugates in the urine and, to a lesser extent, in the faeces. (JECFA 2007)

Excretion:

The registered substance, having a molecular weight lower than 300 g/mol, 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 the registered substance, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells

References:

JECFA, 2007. Safety evaluation of certain food additives. Alicyclic ketones, secondary alcohols and related esters. Prepared by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Food Additives Series: 50. IPCS, WHO, Geneva.