Decan-4-olide

Endpoint summary

Description of key information

By oral exposure, both the aliphatic decalactone and the ring-opened hydroxycarboxylic acid can be absorbed from the gastrointestinal tract following oral exposure. Therefore, gamma-decalactone is readily hydrolysed either before absorption or in systemic circulation. 
Following dermal exposure to gamma-decalactone, molecular weight and log Kow (3) 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-decalactone is unlikely to occur or is anticipated to be very limited.
In any case, after systemic absorption, gamma-decalactone 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-nonalactone, Ɣ-undecalactone and Ɣ-caprolactone data are considered in this dossier in a read-across approach to fill-in the endpoints for Ɣ-decalactone as demonstrated in the overall justification of the read across presented in section 13.

The forty-ninth joint FAO/WHO Expert Committee on Food Additives (JECFA) evaluated a group of aliphatic lactones used as flavouring substances in food (JECFA, 1998). The majority of the aliphatic lactones have been reported to occur naturally in traditional foods and Ɣ-undecalactone is one of the four aliphatic lactones having the highest usage as flavouring substances. It is also ubiquitous in food occurring mainly in fruits, berries, alcoholic beverages, meats and dairy products. JECFA evaluation of all the data indicated no safety concern associated with intake of Ɣ-nonalactone, Ɣ-decalactone, Ɣ-undelactone and Ɣ-caprolactone (JECFA, 1998). Ɣ-nonalactone and Ɣ-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. The following table indicated the physico-chemical and toxicological data which have been identified in the scope of REACH dossiers and considered as relevant for Ɣ-decalactone toxicokinetics.

Table 7.1: Relevant data for the lactone toxicokinetics

Properties	Ɣ-Caprolactone	Ɣ-Nonalactone	Ɣ-Decalactone	Ɣ-Undecalactone
CAS	695-06-7	104-61-0	706-14-9	104-67-6
Molecular mass	114.14 g/mol	156.23 g/mol	170.25 g/mol	184.28 g/mol
Log Kow at 25°C	0.83	2.5	3	3.6
Water solubility	Soluble 5263 mg/L (extrapolated)	Soluble 2200 mg/L	Soluble 1179 mg/L (interpolated)	Moderately soluble 158 mg/L
Vapour pressure	4.2 Pa	1.9 Pa	0.72 Pa	0.27 Pa
Available reliable toxicological studies
Acute toxicity LD50	Oral: >2000 mg/kg bw Dermal: n.d.	Oral: 6500 mg/kg bw Dermal: >5000 mg/kg bw	Oral: n.d. Dermal: n.d.	Oral: n.d. Dermal: > 2000 mg/kg bw
Irritation	Not skin irritating up to 20% Irritation to eyes: n.d.	Not skin irritating Not irritating to eyes	n.d.	Skin irritation: n.d. Irritation to eyes: n.d.
Sensitisation	Not sensitizing (GPMT)	Not sensitizing in human	n.d.	Not sensitizing (OET)
Mutagenicity	Ames test: negative MLA: n.d. In vitro cytogenicity: negative	Ames test: n.d. MLA: negative In vitro cytogenicity: n.d. In vivo micronucleus: negative	Ames test: negative MLA: n.d. In vitro cytogenicity: n.d.	Ames test: negative MLA: n.d. In vitro cytogenicity: n.d.
Repeated dose toxicity	NOAEL = 1000 mg/kg bw/d (28-day toxicity study)	n.d.	n.d.	n.d.
Toxicity to reproduction	NOAEL = 1000 mg/kg bw/d (pre-developmental toxicity study)	n.d.	n.d.	n.d.

n.d.: no data

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 the 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. Ɣ-nonalactone, Ɣ-decalactone and Ɣ-undecalactone are structurally similar compounds of aliphatic lactones as justified in section 13. They are formed by acid-catalysed intramolecular cyclization of 4-carbon hydroxycarboxylic acids to yield five-(gamma-) membered lactone rings. 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.

Toxicokinetics, distribution and excretion by oral route:

It is anticipated that in acidic media, such as stomach (or urine), the Ɣ-decalactone 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, Ɣ-decalactone is readily hydrolysed either before absorption or in systemic circulation. Then linear saturated 4-hydroxycarboxylic acids are converted, via acetyl coenzyme A, to alpha-hydroxythioesters which then undergo alpha-oxidation and alpha-decarboxylation to yield an acetyl CoA fragment and a new alpha-hydroxythioester reduced by 2 carbons. Even-numbered carbon acids continue to be oxidized and cleaved to yield metabolites that are completely metabolized in the citric acid cycle and excreted from the body as CO2, glucuronic acid or sulfate conjugates in the urine and, to a lesser extent, in the faeces. Therefore, Ɣ-decalactone is expected to be efficiently metabolized to innocuous products without saturation of the metabolic pathways.

Toxicokinetics, distribution and excretion by dermal route:

Following dermal exposure to Ɣ-decalactone, molecular weight and log Kow (3) values are in favour of dermal absorption which however should be limited considering the moderate water solubility of the substance. This is corroborated by the in vitro dermal absorption study performed on porcine ear skin exposed to Ɣ-caprolactone which did not penetrate the skin in detectable amounts (Wallny, 2002) whereas Ɣ-caprolactone is considered as dermal absorption worst-case for the linear saturated 4-hydroxycarboxylic acid derived-lactones based on its physico-chemical properties. However, it is likely Ɣ-decalactone will be distributed as ring-opened hydroxycarboxylic acid in blood if very low amounts are dermal absorbed, then metabolized to innocuous metabolites which may be conjugated in order to be excreted mainly in urine. Moreover, in the absence of skin irritation, no damage to the skin surface should occur which may enhance penetration.

Toxicokinetics, distribution and excretion by inhalation:

Considering the low vapor pressure, exposure by inhalation to Ɣ-decalactone is unlikely to occur or is anticipated to be very limited. In this last case, as potential absorption following ingestion is expected (see above), it is likely Ɣ-decalactone will also be absorbed if it is inhaled, be distributed as ring-opened hydroxycarboxylic acid in the blood, metabolized to innocuous metabolites which may be conjugated in order to be excreted mainly in urine.

References:

- Cramer G.M., Ford, R.A. & Hall, R.L. (1978) Estimation of toxic hazard

- A decision tree approach. Food Cosmet.Toxicol., 16, 255–276. -JECFA (1998) Aliphatic lactones. WHO food additives series 40.