6-methylhept-5-en-2-one

Endpoint summary

Description of key information

REACH indicates that an “assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information” should be performed at Annex VIII level. Methyl heptenone is at Annex VIII level and the following evaluation based on data from toxicity studies, physico chemical data, andin silicomodelling has been undertaken: 

 

Data from toxicity studies

Available toxicity studies (90 day oral rat and a prenatal developmental toxicity rat study) with Methyl heptenone did not include plasma level measurements of the test substance. Therefore, there is no direct data to clarify the extent of systemic availability of the parent molecule.

 

Physico-chemical data

Molecular weight: 126.2 g/mol

Physical form at room temperature: colourless to pale yellow clear liquid

Water solubility: 3.02 g/l at 25°C (BASF AG, 1989a).

Partition coefficient, Log Kow = 2.4 (BASF AG, 1989b).

Vapour pressure: 0.99 hPa at 18.18°C; 1.99 hPa at 27.99°C (BASF AG, 1999).

 

ADME data

No specific metabolism studies have been performed with Methyl heptenone or could be located in the literature (SciFinder search, Oct 2016).

 

Methyl heptenone was evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) as one of flavouring substances in the group of the aliphatic secondary alcohols, ketones and related esters (JECFA, 2003). According to JECFA, methyl heptenone has been reported to occur naturally in fruits such as apricots, apples and nectarines. As a flavouring substance, its estimated intake is 120 µg/capita/day in the EU and 44 µg/capita/day in the US based on the Maximised Survey-derived Daily Intake approach.

 

In its evaluation, JECFA stated that Methyl heptenone along with other members in the group of the aliphatic secondary alcohols, ketones and related esters is expected to be metabolized to innocuous products. “After oral administration, aliphatic secondary alcohols and ketones are absorbed through the gastrointestinal tract and subsequently rapidly eliminated from the blood. Peak blood concentrations normally occur within 1–2 h after dosing. Although ketones and secondary alcohols are readily interconverted, reduction of the ketones by cytosolic carbonyl reductases is favoured in vivo, yielding the corresponding secondary alcohols, which are excreted in the urine mainly as glucuronic acid conjugates.

In the case of a methyl ketone, the terminal methyl group may undergo oxidation, eventually yielding alpha-ketoacid (Fig.1). The ketoacids are intermediary metabolites (e.g. alpha-ketoacids) that undergo oxidative decarboxylation to yield carbon dioxide and simple aliphatic carboxylic acids. The acids may be completely metabolized in the fatty acid pathway and citric acid cycle” (JECFA, 2003).

Fig. 1. Metabolic fate of aliphatic ketones and secondary alcohols (see attachment).

In silico prediction of the Methyl heptenone metabolism following oral absorption in mammals (using Meteor Nexus: 3.0.0) indicated that allylic hydroxylation and reduction of the ketone are plausible (refer to Annex 1). No first step reactions were predicted at a probable level. Subsequent oxidation of alcohols and glucuronidation are also predicted as plausible. Such metabolic steps will result in more polar molecules that can be readily excreted via the urinary system. In addition, Methyl heptenone has a Log Kow value below 3, which does not favour fat deposition. Therefore, consistent with JECFA evaluation (JECFA, 2003), in the event of systemic exposure Methyl heptenone will be metabolised to more water-soluble molecules that can be excreted. Overall, systemic accumulation of Methyl heptenone is considered very unlikely.

 

Oral /GI absorption

Systemic biological effects involving kidney, liver and testes were seen in the oral 13 week rat study (BASF AG, 2002a) at the high dose of 1000 mg/kg bw/day. The kidney effects in the males were observed in all dose groups (50, 200 and 1000 mg/kg bw/day). Changes in clinical chemistry parameters were shown in females at 200 mg/kg bw/day. 

Similarly, in a prenatal developmental toxicity study according to OECD TG 414 with gavage application, maternal and prenatal developmental toxicity was found at 1000 mg/kg bw/day (BASF AG, 2002b).

This indirectly indicates that Methyl heptenone can be absorbed by the oral route. Further, the centrolubular liver cell hypertrophy observed in the above mentioned subchronic gavage rat study (BASF AG, 2002a) at a dosage of 1,000 mg/kg/d suggests that the substance is metabolized by the liver.

 

The molecular weight of Methyl heptenone (126.2) is in the range (MW under 500 D) which favours oral absorption, as well as the Log Pow (2.4) is in the range for passive oral absorption (log Pow in range -1 to +4). The water solubility is relatively moderate. Therefore, based on these physico-chemical data, a moderate oral absorption is expected.

 

Summary

Results from an oral toxicity study in rats with up to 3 months exposure indicated, based on indirect evidence, that there is some systemic availability of Methyl heptenone or metabolites at all tested doses. Direct evidence in the form of plasma data is not available. The predicted phase I and phase II metabolism of Methyl heptenone indicates metabolism that will enable excretion and hence the lack of systemic accumulation. Therefore there is no expectation of greater systemic toxicity following longer term exposure.

Annex 1: Meteor prediction (see attachment)

Annex 2: Meteor report (see attachment)

References

BASF AG, 1989a, Analytical Laboratory, Dampfdruck: 2-Methyl-2-hepten-6-on, unpublished study, BRU 89.117, 09 May 1989

BASF AG, 1989b, Analytical Laboratory, Bestimmung des Verteilungskoeffizienten log Pow der Prüfsubstanzen in 1-Octanol/Wasser bei 25°C, unpublished study, J. No. 106288/13, 08 May 1989

BASF AG, 1999, Substance data service, Dampfdruck von 2-Methyl-2-hepten-6-on, unpublished study, report No. 99.271, 06 April 1999

BASF AG, 2002a, Product Safety, 6-Methylhept-5-en-2-one (Methylheptenon) Subchronic toxicity study in Wistar rats, administration by gavage for 3 months, unpublished report, project no. 51S0874/00114, 00/874, 05 Dec. 2002

BASF AG, 2002ab, Product Safety, 6-Methylhept-5-en-2-one (methylheptenon) - Prenatal developmental toxicity study in Wistar rats, oral administration (gavage), unpublished report, project no. 30R0874/00111, 00/874, 29 Oct. 2002

JECFA, 2003. Safety evaluation of certain food additives. Fifty-ninth Meeting of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additives Series: 50. IPCS, WHO, Geneva.