Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

By oral exposure, both the aliphatic undecalactone and the chain-opened hydroxycarboxylic acid can be absorbed from the gastrointestinal tract following oral exposure. Therefore, gamma-undecalactone is readily hydrolysed either before absorption or in systemic circulation.

Following dermal exposure to gamma-undecalactone, molecular weight and log Kow (3.6) values are in favour of dermal absorption which however should be limited considering the moderate water solubility of the substance.

Considering the low vapor pressure, exposure by inhalation to gamma-undecalactone is unlikely to occur or is anticipated to be very limited.

In any case, after systemic absorption, gamma-undecalactone is expected to be efficiently metabolized to innocuous products without saturation of the metabolic pathways.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Ɣ-butyrolactone, delta-verolactone,Ɣ-decalactone, Ɣ-nonalactone and Ɣ-caprolactone data are considered in this dossier in a read across approach to fill-in the endpoints for Ɣ-undecalactone as demonstrated in the overall justification of the read across presented in section 13 (RAAF document).

The toxicokinetic profile of lactones is not determined of absorption, distribution, metabolism or excretion measurements even if a few studies considered as not reliable existed. Rather, the overall physical chemical properties of lactones, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from mutagenicity assays were used to predict the toxicokinetic behavior.

γ-butyrolactone, γ-caprolactone, γ-nonalactone, γ-decalactone, γ-undecalactone and δ-valerolactone are structurally similar compounds of aliphatic lactones considered this read-across approach. All aliphatic lactones are formed by acid-catalysed intramolecular cyclization of 4-carbon hydroxycarboxylic acids to yield five- or six-(gamma-) membered lactone rings. They differ with respectively no branching, or ethyl, pentyl, hexyl or heptyl branch on C5.d-Valerolactone is the analogue unbranched ring of 5-carbon acid, i.e. six-(delta-) membered lactone. The stability of the lactone ring in an aqueous environment is pH-dependent since a pH-equilibrium is established between the open-chain hydroxycarboxylic acid and the lactone ring.

Consequently, all of the source and the target substances have similar mechanism of action (MechoA 2.1) which is enzymatic hydrolysis into narcotic products, i.e. membrane destabilisers (iSafeRat® Online, v2.0). However, the rate of hydrolysis might be different between the target and source substances depending on the cycle and on the substitution of the lactone. Hence, γ-butyrolactone a lactone with a 5-membered cycle should be hydrolysed at higher rate than lactone with a 6-membered cycle such as δ-Valerolactone. Moreover, an aliphatic lactone substituted with an alkyl group on the carbon holding the cyclic oxygen (i.e. gamma position for γ-lactones) as γ-Caprolactone would also be hydrolysed at higher rate than an unsubstituted lactone (i.e. γ-Butyrolactone).

Finally, based on these hypotheses, γ-Butyrolactone could be the worst-case source substance for narcotic effects if the hydrolysis rate is the lowest and if this lactone form induces narcotic effects.

 Therefore, the structural differences due to substitution with an alkyl group together with the alkyl branch length, or additional carbon in cycle, have impact on the key physico-chemical properties allowing extrapolation in the assessment of the toxicological properties of interest between the source and the five target substances.

 

Absorption

In experimental supporting studies on hydrolysis, incubation of γ-undecalactone with 50 mL of simulated intestinal fluid resulted in 58% hydrolysis within 4 h, yielding the ring-opened hydroxycarboxylic acids. Doubling the volume of intestinal fluid resulted in a 62% hydrolysis of γ-undecalactone, within the same period of time (Morgareidge, 1962).

Incubation of γ-nonalactone and γ-undecalactone with rat liver homogenate in buffer solution at pH 7.5 resulted in 62–94% and 26–40% hydrolysis within 1 h, respectively. After 1 h, 81–88% and 45–70% hydrolysis of γ-nonalactone and γ-undecalactone, respectively, occurred at pH 8.0 (Morgareidge, 1963).

Therefore, it is anticipated that in acidic media, such as stomach (or urine), γ-undecalactone ring is favoured while in basic media, such as intestines (or blood), the open-chain hydroxycarboxylate anion is favoured. Both the aliphatic lactones and the ring-opened hydroxycarboxylic acids can be absorbed from the gastrointestinal tract following oral exposure.

Therefore, γ-undecalactone is readily hydrolysed either before absorption or in systemic circulation.

Following dermal exposure to γ-undecalactone, molecular weight and log Kow (3.6) values are in favour of dermal absorption which however should be limited considering the moderate water solubility of the substance (0.158 g/L). This is corroborated by the in vitro dermal absorption study performed on porcine ear skin exposed to γ-Caprolactone which did not penetrate the skin in detectable amounts (Wallny, 2002) whereas γ-caprolactone is considered as dermal absorption worst-case for the linear saturated 4-hydroxycarboxylic acid derived-lactones based on its physico-chemical properties (LogKow = 0.3 and WS= 77 g/L).

Moreover, in the absence of skin irritation, no damage to the skin should occur which may enhance penetration.

Considering the low vapor pressure, exposure by inhalation to γ-undecalactone is unlikely to occur or is anticipated to be very limited. In this last case, as potential absorption following ingestion is expected, it is likely γ-undecalactone will also be absorbed if it is inhaled.

 

Distribution

Following oral absorption or absorption by inhalation, the aliphatic lactones and their ring-opened acids can be distributed in the different organs via the systemic circulation.

 

Metabolism

In the blood, lactones would be hydrolysed rapidly to the open-chain hydroxycarboxylic acid. Studies showed that hydroxycarboxylic acids are rapidly metabolized. In fact, on the basis of the results of studies performed using structurally-related γ-lactones (length of carbon chain from C4 to C16), the hydroxycarboxylic acids resulting from hydrolysed aliphatic lactones, are converted via acetyl coenzyme A into the corresponding hydroxy-thioesters. Then, these compounds undergo α-oxidative decarboxylation to yield metabolites that are completely metabolized in the citric acid cycle.

Therefore, γ-undecalactone is expected to be efficiently metabolized to innocuous products without saturation of the metabolic pathways.

 

Excretion

Studies showed that once metabolized, the compounds are excreted predominantly in the urine. Indeed, they are excreted from the body as CO2, glucuronic acid or sulfate conjugates in the urine and, to a lesser extent, in the faeces (JECFA, 1998).

Finally, the forty-ninth joint FAO/WHO Expert Committee on Food Additives evaluated a group of aliphatic lactones used as flavouring substances in food and all the data indicated no safety concern associated with intake ofγ-nonalactone,γ-decalactone,γ-undecalactone andγ-caprolactone (JECFA, Aliphatic lactones. WHO food additives series 40, 1998).γ-nonalactone andγ-undecalactone have been evaluated previously at the Eleventh Meeting of the Committee and an ADI of 1.25 mg/kg b.w. was established for each substance.