Octan-4-olide

Endpoint summary

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance octan-4-olide is an organic mono-constituent with a purity of ≥ 99% to <100%, with the typical concentration of ≥ 99%.

A full ADME toxicokinetic study in the rat is not available. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has concluded on the absorption, metabolism and elimination of the aliphatic lactones, including octan-4-olide [1]. The toxicokinetic analysis is based on the JECFA report, physicochemical and in vivo toxicological data. In vivo studies in rats covering the oral route (acute toxicity study, read-across repeated dose toxicity (28 days) with hexan-4-olide (CAS No. 695-06-7), read-across pre-natal developmental toxicity study with hexan-4-olide (CAS No. 695-06-7)) and the dermal route (read-across guinea pig maximisation test with hexan-4-olide (CAS No. 695-06-7). No studies via the inhalation route are available. Further details on the endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical data, literature and available in vivo toxicological data, octan-4-olide is expected to be absorbed via the oral, dermal and inhalation routes. In acidic media e.g. stomach or urine, the lactone ring formations are favoured while in basic media e.g blood or intestines, the open-chain hydroxycarboxylate anions are favoured. Octan-4-olide will be distributed throughout the body and is unlikely to accumulate. Octan-4-olide is predicted to be efficiently metabolised via commonly known biochemical pathways to innocuous products and excreted in the urine.

The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

1.Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of octan-4-olide in the body.

Absorption - oral

The molecular weight of octan-4-olide (142 g/mol) is in the range for favourable oral absorption (<500 g/mol). As a water-soluble substance, (8096 mg/L at 20°C), octan-4-olide should readily dissolve in the gastrointestinal fluids. The molecular weight is low (<200 g/mol) so it may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The log Kow of octan-4-olide (1.89 at 25°C) is in the range favourable for passive diffusion.

Absorption – dermal

The molecular weight, log Kow and water solubility of octan-4-olide is in the favourable range for dermal absorption.

Absorption – inhalation

Octan-4-olide has a low volatility (0.1 kPa at 20°C), so exposure via the inhalation route is expected to be low. However due to the end use as a flavouring that can generate an aroma, exposure via the inhalation route will be considered. As a liquid, octan-4-olide would readily diffuse/dissolve into the mucus lining the respiratory tract and it is sufficiently lipophilic (log Kow 1.89) to be absorbed directly across the respiratory tract epithelium. However, as a very hydrophilic substance with a molecular weight <200 g/mol, it may also be absorbed through aqueous pores or retained in the mucus and transported out of the respiratory tract.

2. Other data in the literature

Lactones are generally formed by acid-catalysed intramolecular cyclization of hydroxycarboxylic acids [1]. In an aqueous environment, a pH-dependent equilibrium is established between the open-chain hydroxycarboxylate anion and the lactone ring. In basic media, such as blood or intestines, the open-chain hydroxycarboxylate anion is favoured while in acidic media, such as urine or the stomach, the lactone ring is favoured. Both the aliphatic lactone and the ring-opened hydroxycarboxylic acids can be absorbed from the gastrointestinal tract. The JECFA places octan-4-olide in the saturated linear hydroxycarboxylic acid sub-group of aliphatic lactones, based on their predicted metabolism [1]. It is predicted to be efficiently metabolised via commonly known biochemical pathways to innocuous products. More specifically, linear saturated 4-hydroxycarboxylic acids (formed from γ-lactones) are converted, via acetyl coenzyme A, to hydroxythioesters which then undergo ß-oxidation and cleavage to yield an acetyl CoA fragment. Loss of this fragment produces an alpha-hydroxythioester which undergoes alpha-oxidation and alpha-decarboxylation to yield a linear carboxylic acid and eventually carbon dioxide.

3. Information from other studies in the dossier

Absorption - oral

In an acute oral toxicity study (equivalent or similar to OECD 401), 10 rats were given octan-4-olide at doses of 5000 mg/kg bw. No mortalities were observed and lethargy was noted. The LD50 was > 5000 mg/kg bw

.

In a read-across sub-acute toxicity study (OECD 407/GLP), hexan-4-olide (97.5%) was administered by gavage to Crl:CD(SD)IGS BR rats (5/sex/group) in water at 30, 100, 300 or 1000 mg/kg bw/day for 28 days. Satellite groups (5/sex) were included for control and high dose treatments for evaluation of a 14-day recovery period. All animals survived to the scheduled necropsies. Body weights, food consumption, hematology and urinalysis parameters were unaffected by test article administration. There were no effects on functional observational battery parameters or locomotor activity. No test article-related ophthalmic findings were noted. No test article-related changes were noted in the 30, 100 or 300 mg/kg bw/day groups. At 1000 mg/kg bw/day, slightly increased incidence of wet and/or dried material (clear, red and/or yellow) around the mouth and/or the urogenital area of forelimb at low incidence at the time of dosing (females) and one hour following dosing (males and females) was noted. These findings were not considered to be adverse. Lower mean cholesterol levels (males and females) were also noted but were not considered to be adverse. Increased mean liver weights (absolute and/or relative to final body and/or brain weights) were noted for both males and females at the primary (week 4) necropsy. This increase was not observed at the recovery period. Pale liver was noted in two males and four females at the primary necropsy and correlated with the increased lipid bodies seen by election microscopy. No conclusive test article-related light microscopic findings were noted. However, a very slight increase in the incidence of cytoplasmic vacuolation was observed in one male and two females in the 1000 mg/kg bw/day group. This observation may explain the increased liver weights and ultrastructural findings. Marked increase in lipid bodies and a slight increase in dark glycogen granules within the hepatocytes of those livers examined by electron microscopy. The increased lipid bodies may account for the increased liver weights and the gross observations of pale liver, particularly in females. Based on the results of this study, the NOEL was 300 mg/kg bw/day and the NOAEL was 1000 mg/kg bw/day. The effects noted at the 1000 mg/kg bw/day were very minimal and not indicative of significant toxicity. There was no evidence of liver toxicity. The higher liver weights, the slightly higher incidence of hepatic cytoplasmic vacuolation observed by light microscopy in the females and the higher incidence of lipid bodies and dark glycogen granules observed by electron microscopy were most likely a physiological adaptation to the administration of the test article. Consequently, they were not considered as adverse. Furthermore, the changes were reversible as they were no longer observed following the 14-day recovery period. The predicted NOAEL for octan-4-olide is also 1000 mg/kg bw/day.

In a read-across developmental toxicity study (OECD 414/GLP), hexan-4-olide (97.5%) was administered to 25 females Crl:CD(SD)IGS BR rats/dose by gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day from days 6 through 19 of gestation. All animals survived to the scheduled necropsy on GD20. There were no test article-related maternal clinical observations or effects on mean body weights, body weight gains, net body weights, net body weight gains, gravid uterine weights or food consumption at any dose level. There were no test article-related internal findings at the scheduled necropsy. The mean fetal sex ratio and mean numbers and/or litter proportions of viable fetuses and pre- and post-implantation losses in the 1000 mg/kg bw/day group were not affected by test article administration. Intrauterine growth and survival were unaffected in the 100 and 300 mg/kg bw/day groups. No test article-related fetal malformations or developmental variations were noted at any dose level in this study. Test article-related effects noted in the 1000 mg/kg bw/day group consisted of statistically significant reduced mean fetal body weight (5.6 % lower than the control group value for combined fetal weight). This slight decrease was not considered of toxicological concern. No other indicators of developmental toxicity were noted. Based on the results of this study, the dose level of 1000 mg/kg bw/day was considered to be the NOAEL for maternal toxicity and the dose level of 1000 mg/kg bw/day was considered to the NOAEL for developmental toxicity. The predicted NOAEL (maternal/developmental) for octan-4-olide is also 1000 mg/kg bw/day.

Based on the physicochemical data and available in vivo toxicological data, there is systemic absorption after oral administration. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

Absorption – dermal

In a dermal sensitization study (equivalent or similar to OECD406/GLP) with hexan-4-olide (97.4%) in physiological saline, young female Hartley albino guinea pigs were tested in a maximisation test. For induction, 3% hexan-4-olide in physiological saline (intradermal injections) and undiluted hexan-4-olide in physiological saline (topical application) was used. For challenge, 3, 5, 10, 30, 50% and undiluted hexan-4-olide in water was used for topical application. The evaluation of skin reactions after challenge was carried out at 24 and 48 hrs. The positive control, 2,4-dinitrochlorobenzene, gave the appropriate response. No positive reactions were evident after the first challenge application at 24 or 48 hours, neither when treated with physiological saline alone nor when treated with 3, 5, 10, 30, 50% and undiluted test article dilutions. The substance was not sensitising. Octan-4-olide is also predicted not to be sensitising. Octan-4-olide is a skin irritant and the read-across source substance hexan-4-olide is also predicted to be an irritant, so similar dermal bioavailability is expected.

Based on the physicochemical data and available in vivo toxicological data, there is some systemic absorption after dermal administration. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Absorption – inhalation

There is no inhalational toxicity study in rats available. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, using a conservative approach.

Distribution/Metabolism/Excretion

Based on the physicochemical data, literature and available in vivo toxicological data, in acidic media e.g. stomach or urine, the lactone ring formations are favoured while in basic media e.g blood or intestines, the open-chain hydroxycarboxylate anions are favoured. Octan-4-olide will be distributed throughout the body and is unlikely to accumulate. Octan-4-olide is predicted to be efficiently metabolised via commonly known biochemical pathways to innocuous products and excreted in the urine.

1. JECFA (1998). Evaluation of certain food additives and contaminants. WHO Technical Report Series: 884. Prepared by the forty-ninth meeting of the JECFA. World Health Organization, Geneva