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Description of key information

The available evidence suggests that the substance is bioavailable via the oral and dermal route. Systemic absorption of this substance via inhalation route is expected but to a limited extent. 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 registered 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 its analogue, 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 registered substance is the cis isomer of the analogue substance, having a relatively low molecular weight of 226.31 g/mol. The substance is a moderately water soluble liquid (574 mg/L, data from analogue) and is moderately lipophilic based on the octanol/water partition coefficient (log Kow = 2.79, data from analogue). The water solubility and log Kow data from the analogue are considered to be relevant to assess the toxicokinetic behaviour of the registered substance as no significant difference is anticipated between the isomers. The registered substance has low volatility according to its vapour pressure (0.0874 Pa at 20°C, data from analogue).

Absorption:

The physical chemical characteristics described above suggest that the registered substance is absorbed in the gastro-intestinal tract by passive diffusion. Mortality and clinical signs of narcosis were observed at high dose levels (10000 mg/kg bw) in the acute oral gavage toxicity studies conducted on different qualities of the analogue substance (LD50 > 5000 mg/kg bw). Taken together, the repeated dose studies (a 90-day study using diet, a 28-day study using gavage), the reproduction/developmental screening test and the pre-natal developmental toxicity study conducted on the analogue substance gave a NOAEL of 1000 mg/kg bw/day. Changes observed in liver and kidneys 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. Based on the results of the acute oral toxicity study, the absence of effects in the repeated toxicity studies probably indicates low toxicity rather than the absence of absorption. There are no ionisable groups in the parent substance so pH would not affect absorption.

Regarding dermal absorption, systemic absorption by the dermal route is expected to be moderate to high based on the Log P and the water solubility values. This is supported by an in vitro skin absorption study which indicated that the percutaneous absorption level of the analogue substance was significant. The test substance permeated the skin fairly rapidly, but the permeation subsequently plateaued somewhat as the donor phase became depleted through both evaporation and loss due to permeation. Following 48 hours exposure, 45.9 ± 3.5% of the applied dose (mean ± standard error, se) had permeated into the receptor phase. Systemic effects following single-dose dermal application of the analogue substance up to 5000 mg/kg bw also suggests than systemic absorption through cutaneous barriers has occurred.

The potential for inhalation toxicity was not evaluated in vivo. However, the vapour pressure of the analogue substance indicated a low 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.

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 metabolization the substance as such would not accumulate in the body fat.

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 registered substance. The registered substance is predicted to be hydrolysed by tissues esterases into its acid form and alcohol and then undergoes beta oxidation and subsequent ring cleavage and/or aromatization of the ring and/or can be excreted in urine as cyclic carboxylic acid and its glycine and glucuronide conjugates.

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:

- WHO Technical Report Series 913. Evaluation of certain food additives. Fifty-ninth report of the Joint FAO / WHO Expert Committee on Food Additives

- WHO Technical Report Series 8913. Evaluation of certain food additives. Fifty-first report of the Joint FAO / WHO Expert Committee on Food Additives

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