Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

The available evidence suggests that the substance is bioavailable via the oral route. Systemic absorption of this substance via inhalation and dermal routes is expected but to a limited extent. The substance is expected to be mainly excreted in urine.The substance has a potential to bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

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 target substance and the source substance, 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.

 

Physical-chemical properties:

The target and source substances are structurally related, in that both are trans-3,3-dimethyl-5-(2,2,3-trimethyl-cyclopent-3-en-1-yl)pent-4-en-2-ol (MW = 222.37 g/mol). As two asymmetric (chiral) carbon atoms are present in this chemical structure, the chemical exists as 2x2=4 enantiomers: RR, RS, SR and SS forms. The target substance is a reaction-mass between two of these stereoisomers (RS and SS) whereas the target substance is a mixture of the two others (SR and RR). [Cf. Read-across justification document in Iuclid section 13 for further justification).

The target substance is a slightly water soluble liquid (10.3 mg/L) and is highly lipophilic based on the octanol/water partition coefficient (log Kow = 4.99).

The source substance is a slightly water soluble liquid (13.2 mg/L), is highly lipophilic based on the octanol/water partition coefficient (log Kow = 4.99) and has low volatility according to its vapour pressure (1.5 Pa at 25°C).

 

Absorption:

Oral/GI absorption

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

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

- An acute oral gavage toxicity study conducted on the target substance identified neither mortality nor clinical signs (LD50 > 2000 mg/kg bw).

- The repeated dose studies (a 90-day study, a 28-day study), a reproduction/developmental screening conducted on the target substance using the oral route (gavage) gave a NOAEL of 1000 mg/kg bw/day. Changes observed in liver and kidneys in the 90-day study were considered as a normal adaptive metabolism/excretion response following administration of a xenobiotic. In the absence of corroborative pathology or functional change of the organs these changes are considered not to be adverse. No treatment-related effects were observed in any of these studies.

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 target substance being lipophilic (log Kow = 4.99), 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 target substance. Even if the target substance is considered to be a skin irritant based on source substance data, and may enhance penetration and therefore enhance the dermal uptake, the absence of systemic effects following a single-dose dermal application of the source substance up to 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.

However, the vapour pressure of the source substance (1.5 at 20°C) indicated an absence of volatility and inhalability 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.

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 target 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 target 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 target substance may readily cross cellular barriers or may be distributed into fatty tissues with a low 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:

The WHO International Programme on Chemical Safety has made a safety evaluation of certain food additives and contaminants. This report describes the likely metabolic route for various Alicyclic Primary Alcohols, Aldehydes, Acids, and Related Esters, including substances structurally-related to the target substance. The oxygenated side-chain is predicted to be the main site of oxidative metabolism prior to excretion of more polar acid metabolites.

Alternatively, the alcohol group may be conjugated to glucuronide or sulphate without any further oxidation.

 

Excretion:

The target 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 target substance, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.

 

Reference:

- JECFA (2000) ALIPHATIC PRIMARY ALCOHOLS, ALDEHYDES, ACIDS, AND RELATED ESTERS.WHO food additives series 40.