(S)-(+)-Carvone (D Carvone) is a naturally occurring compound present in several food products and used to flavor foods. Carvone occurs naturally as dextrorotatory (d-) and levorotatory (l-) enantiomers in several food items; these may also be used as a pesticide, food flavouring, feed flavouring, in feed additive, in personal care products and as (veterinary) medicine. In order to improve coherence regarding the risk assessment of carvone in the different food and feed sector areas, EFSA asked its Scientific Committee to establish a single ADI for carvone, estimate the overall exposure of European consumers, and quantify the contribution for each source of exposure to the overall exposure of carvone. Having reviewed the information available the Scientific Committee decided to address dcarvone and l-carvone separately and limit its assessment to the oral intake of d- and l-carvone. The Scientific Committee established an ADI of 0.6 mg/kg bw/day for d-carvone, based on the BMDL10 of 60 mg/kg bw/day for an increase in relative liver weight in the rat 90-day studies and an uncertainty factor of 100. The Scientific Committee could not establish an ADI for l-carvone because of a lack of toxicological data for this enantiomer. The highest level of aggregated exposure to d-carvone is estimated to be 0.60 mg/kg bw/day, i.e. is at the level of the ADI established for d-carvone. The highest level of aggregated exposure to l-carvone is three-fold that of d-carvone. In view of key uncertainties 1) on the toxicity of l-carvone, 2) on the biological relevance of the endpoint selected to establish the ADI for d-carvone and its use as a surrogate for the observed lethality in tested animals, 3) whether d- and l-carvone should be considered together for possible combined effects and 4) in the aggregated exposure assessments to d- and to l-carvone, the Scientific Committee recommended generating additional data to refine the current risk assessment [1].

Physicochemical Properties

Molecular Formula	C10H14O
Molecular Weight	150.2176
Exact Mass	150.104
CAS #	2244-16-8
Related CAS #	(-)-Carvone;6485-40-1
PubChem CID	16724
Appearance	Colorless to light yellow liquid
Density	0.9±0.1 g/cm3
Boiling Point	230.5±35.0 °C at 760 mmHg
Melting Point	25.2ºC
Flash Point	88.9±0.0 °C
Vapour Pressure	0.1±0.5 mmHg at 25°C
Index of Refraction	1.481
LogP	2.27
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	1
Rotatable Bond Count	1
Heavy Atom Count	11
Complexity	223
Defined Atom Stereocenter Count	1
SMILES	O=C1C(C([H])([H])[H])=C([H])C([H])([H])[C@]([H])(C(=C([H])[H])C([H])([H])[H])C1([H])[H]
InChi Key	ULDHMXUKGWMISQ-VIFPVBQESA-N
InChi Code	InChI=1S/C10H14O/c1-7(2)9-5-4-8(3)10(11)6-9/h4,9H,1,5-6H2,2-3H3/t9-/m0/s1
Chemical Name	(5S)-2-methyl-5-prop-1-en-2-ylcyclohex-2-en-1-one
Synonyms	d-Carvone; 2244-16-8; (S)-(+)-Carvone; (+)-Carvone; (S)-Carvone; (S)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-enone; Carvone, (+)-; D(+)-Carvone;
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	Naturally occuring flavor
ln Vitro	In the caraway fruit, d-carvone is biosynthesised through a multi-step pathway starting from geranyl diphosphate which is firstly cyclised to d-limonene, then stored in essential oil ducts, further converted to d-trans-carveol by limonene-6-hydroxylase, and finally oxidised by a dehydrogenase to d-carvone (Bouwmeester et al., 1998). In a similar fashion, l-carvone is synthesised in the glandular trichomes of spearmint (Mentha spicata) through the cyclisation of the C10 isoprenoid intermediate geranyl pyrophosphate to the monoterpene hydrocarbon l-limonene then hydroxylated to l-carveol and subsequently dehydrogenated to l-carvone (Gerchenzon et al., 1989) [1].
ln Vivo	Activities in the field of food flavourings Regarding the evaluation of carvone in food, the genotoxicity of d-carvone was evaluated by the JECFA; it was concluded that d-carvone was not genotoxic and was not carcinogenic in mice. This evaluation of the JECFA was endorsed by the CEF Panel and d-carvone together with the structurally related l-carvone were cleared with respect to genotoxicity (EFSA CEF Panel, 2011a). Considering that the JECFA evaluated the two substances before 2000 and that no safety concerns were identified by the JECFA, EFSA was not required to re-evaluate their safety, in line with the provisions laid down in Commission Regulation (EC) No 1565/20006 . Accordingly, both substances were included in the European Union list of flavouring substances in Regulation (EU) No 872/2012 (EU, 2012) [1].
Toxicity/Toxicokinetics	16724 rat LD50 oral 3710 uL/kg Food and Cosmetics Toxicology., 16(673), 1978 16724 rabbit LD50 skin 4 mL/kg SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE Food and Cosmetics Toxicology., 16(673), 1978 The Committee did not re-evaluate (+)-carvone (No. 380.1) according to the revised Procedure for the Safety Evaluation of Flavouring Agents given the lack of information on the oral exposure from all sources and the need to review the ADI. A review of the ADI is recommended based on the evaluation of all biochemical and toxicological data. Also, data are needed for an exposure assessment for oral exposure to (+)-carvone from all sources to complete the evaluation for (+)-carvone.
References	[1]. Scientific Opinion on the safety assessment of carvone, considering all sources of exposure.European Food Safety Authority (EFSA), Parma, Italy.
Additional Infomation	D-carvone appears as pale yellow or colorless liquid. (NTP, 1992) (+)-carvone is a carvone having (S) configuration. It is an enantiomer of a (-)-carvone. d-Carvone has been reported in Camellia sinensis, Angelica gigas, and other organisms with data available. See also: Caraway Oil (part of). Carvone is a natural component in several food items such as mint and caraway but it may also be used as a pesticide, food flavouring, feed flavouring or, together with other active substances, in a zootechnical feed additive. Evaluations of this compound have therefore been performed by different scientific bodies and by the European Commission: initially by the Joint FAO/WHO Committee on Food Additives (JECFA) between 1968 and 2000, then as a pesticide active substance by the European Commission in 2008 (in application of Directive 91/414/EEC4 , repealed by Regulation (EC) No 1107/20095 ), then by the EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) in 2011 and the latest evaluation by EFSA's Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) in 2011. The JECFA established an acceptable daily intake (ADI) of 0-1 mg/kg body weight per day based on short-term studies in rats (WHO, 2000, 2004). The Standing Committee on the Food Chain and Animal Health (SCoFCAH) of the European Commission (EC) established an ADI of 0-0.025 mg/kg bodyweight per day based on a different short-term toxicity study in rats (EC, 2008), the CEF and FEEDAP Panels endorsed the assessment done by the JECFA.

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~665.69 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.64 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (16.64 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (16.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	6.6569 mL	33.2845 mL	66.5690 mL
	5 mM	1.3314 mL	6.6569 mL	13.3138 mL
	10 mM	0.6657 mL	3.3285 mL	6.6569 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.