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, dermal and inhalation route. The substance is expected to be mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:
no 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 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 154.25 g/mol. The substance is a moderately water soluble liquid (278.8 mg/L) and is moderately lipophilic based on the octanol/water partition coefficient (Log Kow = 3.3). The substance has low volatility according to its vapour pressure (15.4 Pa at 25°C).

Absorption:

Oral/GI absorption

The physical chemical characteristics described above suggest that the substance is absorbed in the gastro-intestinal tract by passive diffusion.

This hypothesis is supported by signs ofsystemic effects in the oral toxicity studies, as summarized below:

- In an acute oral gavage study, animals were ruffled and depressed within 2 hours after dosing but were normal after 24 hours (LD50 > 5000 mg/kg bw).

- In a 14-Day Dose Range Finding Study for an OECD 422, signs of systemic absorption were observed (effects on body weights and organ weights; male-specific effects on kidneys linked to alpha 2µ globulin)

- 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 at the highest dose tested and below. 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 (non-adverse) 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, systemic absorption by the dermal route is expected to be moderate to high based on the Log Kow and the water solubility values. 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 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 = 14.4 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:

Any material that is absorbed will be distributed via the blood to the liver, and other organs and tissues. The moderate water solubility of the substance would limit distribution in the body via the water channels. The log Kow 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.

Metabolism:

Specific data on metabolism of the registered substance is not available. Metabolism did not influence genotoxicity in Ames test or in vitro gene mutation study in mammalian cells. 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.

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.