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EC number: 943-438-6 | CAS number: 90063-59-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
Litsea cubeba is expected to be readily absorbed, orally and via inhalation but somewhat less via the dermal route, based on study information on constituents and physico-chemical parameters. As adverse effects were observed in the repeated dose studies, route-to-route extrapolation will be performed to estimate the dermal DNELs.
Key value for chemical safety assessment
- Bioaccumulation potential:
- low bioaccumulation potential
- Absorption rate - oral (%):
- 90
- Absorption rate - dermal (%):
- 50
- Absorption rate - inhalation (%):
- 100
Additional information
Toxicokinetic evaluation of Litsea Cubeba oil based on existing data
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.
General information
Litsea Cubeba oil is a substance of Unknown or Variable composition, Complex reaction products or Biological material (UVCB substances), or more specifically a NCS (Natural Complex Substance). As such, Litsea Cubeba oil is an essential oil obtained from the fruits of Litsea cubeba, Lauraceae, obtained by steam distillation and optionally refined by distillation, and consists of the following identified constituents:
Name - Constituent |
CAS Number - Constituent |
Concentration Range in NCS (% w/w) |
Geranial |
141-27-5 |
24.84 – 43 |
Neral |
106-26-3 |
20.24 – 35 |
L-Limonene |
5989-54-8 |
2.3 - 18 |
β-Myrcene |
123-35-3 |
0.74 - 1.8 |
Isogeranial |
72203-98-6 / 55722-59-3 |
0.46 – 2.5 |
α-Pinene |
7785-26-4 |
0.46 - 2 |
1,8-Cineole |
470-82-6 |
0.31 - 1.7 |
Sabinene |
3387-41-5 |
0.20 - 2 |
Nerol |
106-25-2 |
0.18 - 1.2 |
(+)-Citronellal |
2385-77-5 |
< 0.01 - 7 |
Methyl Heptenone |
110-93-0 |
< 0.01 - 5 |
(-)-linalol |
126-91-0 |
< 0.01 - 3.3 |
β-Caryophyllene |
87-44-5 |
< 0.01 - 3 |
Geraniol |
106-24-1 |
< 0.01 - 2.9 |
Verbenol |
473-67-6 |
< 0.01 – 2.2 |
Isoneral |
72203-97-5 |
< 0.01 - 2 |
β-(+)-Citronellol |
1117-61-9 |
< 0.01 - 1.5 |
The main constituents are (E)-3,7-dimethylocta-2,6-dienal (Geranial ; CAS 141-27-5), (Z)-3,7-dimethylocta-2,6-dienal (Neral; CAS 106-26-3) and (S)-p-mentha-1,8-diene (L-Limonene; CAS 5989-54-8), which add up to a percentage range of approximately 47- 96%, andcan therefore be considered representative of the substance.
ADME data
Absorption, distribution, metabolism and excretion data on Litsea Cubeba oil itself are not available and therefore the toxicokinetic assessment is based on the available toxicology data for Litsea Cubeba oil, as well as data for the main constituents.
Information from physico chemical and toxicity studies:
An overview of the relevant physicochemical parameters for Litsea Cubeba oil is provided below.
Parameter |
Litsea Cubeba oil |
Physical state |
Liquid |
Structure |
UVCB / NCB |
Particle size |
Not relevant |
Log Kow |
2.06 - 6.3 (16.90% of the known constituents has a log Kow >= 4) |
Water solubility (mg/l) |
0.5 - 4364 mg/L at 25°C. |
Boiling point (°C) |
83°C at 1013 hPa. |
Vapour pressure |
60.69 Pa at 25°C (The vapour pressure of the constituents range from 1.06 to 981 Pa.) |
Absorption
Oral:As the molecular weight range of this UVCB is below 500, the molecules in this UVCB are likely to be absorbed via the oral/GI tract. Uptake through aqueous pores or carriage of such molecules across membranes with the bulk passage of water in the GI tract can be expected. Furthermore uptake by passive diffusion is likely based on the moderate log Kow values (between -1 and 4) of the constituents within the substance. The oral absorption of the more highly lipophilic constituents of this UVCB (log Kow > 4) may be more dependent on micellar solubilisation.
Based on the previous, the substance can be absorbed in the human body via the oral route. This is supported by the findings in an oral acute toxicity study, in which mortality was observed after 5000 mg/kg bw of Litsea Cubeba oil. Furthermore, in the oral repeated dose study, systemic effects were observed in rats and mice. These findings confirm that systemic absorption of the substance via the gastrointestinal tract takes place.
In addition to the above, some information regarding oral absorption is available for Citral. Citral consists of geranial and neral, which are two of the main constituents of Litsea cubeba oil. Geranial and neral can make up up to 78% of the UVCB. In the disseminated Citral dossier a 90% bioavailability has been set for the oral route, on the basis of available toxicokinetic data which shows rapid and high oral absorption (Diliberto JJ, Usha G, Birnbaum LS, 1988). Therefore, for the derivation of the systemic dermal -DNEL, an oral absorption rate of 90% is assumed.
Dermal:In an acute dermal toxicity study, mortality and clinical signs were observed in rabbits exposed to 2500 mg/kg bw group (1/4 rabbits died), as well as the 5000 mg/kg bw (2/4 rabbits died). Though these findings suggest high dermal absorption, in this study the skin was abraded, thereby promoting its dermal absorption. In the two available OECD TG 404 in vivo skin irritation studies where exposure was done to intact skin, no systemic effects were reported. Even though Litsea cubeba is not a corrosive, the skin irritating properties observed in the in vivo skin irritation test suggest that this UVCB may damage the skin and thereby increase its penetrating potential. As sensitisation is also observed for this substance in an OECD TG 429 study, some uptake must occur. Based on the physico chemical properties of the substance, its molecular weight would not exclude dermal uptake, and its water solubility and logP value would predict low to moderate absorption of at least a part of its constituents (ECHA guidance, 7.12, Table R.7.12-3).
Furthermore, some information regarding dermal absorption is available for geranial and neral, two of the main constituents of Litsea cubeba oil tested in the form of Citral. Even though a large part of Citral is expected to be lost due to evaporation, studies indicate that the remainder has the potential to be absorbed dermally. In an in vivo dermal application study by Diliberto et al. (1988) about 50% of dermally applied Citral was lost due to evaporation and absorption by the application device during dermal administration. However, after 72 hr recoveries were ca. 10% on the treated skin site, ca. 10% in the remaining tissues, ca. 20 or 30% in the excreta (5 or 50 mg/kg-dose groups). Furthermore, Scolnik et al (1994) reported percutaneous absorption into the systemic circulation within 2.5 min after topical application of Citral. Dermal permeability has also been shown in anin vitrostudy by Hayes et al. (2003) in which Citral was absorbed in all layers or freshly excised human skin.
Taken together, the available information on Litsea cubeba oil and its constituents indicate that low to moderate dermal absorption of at least a part of its constituents is to be expected, though the high volatility of the constituents may limit its absorption. Therefore, for the derivation of the systemic dermal DNEL, a dermal penetration rate of 50% is assumed.
Inhalation:Uptake via the lungs, for the highly lipophilic constituents (log Kow >4), with a low water solubility may be mainly via micellar solubilisation. The constituents with a more moderate log Kow values (between -1 and 4) would favour absorption directly across the respiratory tract epithelium by passive diffusion. These physico-chemical properties would also facilitate absorption directly across the respiratory tract epithelium following aspiration.
Distribution
Distribution of Litsea Cubeba oil and its major constituent is expected based on the relatively low molecular weights. Also distribution (of constituents) throughout the body would be possible due to the wide range of water solubilities, while the higher Log Kow range also suggests possible distribution into cells. Signs of toxicity and target organs suggest that the substance is at least distributed to the kidney and bone marrow.
Metabolism
No information on metabolism can be derived from the physicochemical data that is available for Litsea Cubeba oil. For the main constituents of the UVCB L-Limonene, Neral and Geranial, oxidation of the aldehyde group into alcohols is expected, as well as the formation of dicarboxylic acid metabolites and glucuronide conjugates.
Elimination
Based on the renal effects observed in the repeated dose toxicity study, excretion is expected to take place though the kidney. This is supported by the relatively low molecular weights. Excretion via bile is not likely, as in the rat it has been found that substances with molecular weights below 300 do not tend to be excreted into the bile (Renwick, 1994). Some excretion via breast milk, saliva and sweat is cannot be excluded, as some constituents of the UVCP can be regarded as lipophilic (Log Kow > 4).
Accumulation
There is the potential for the more highly lipophilic constituents of this UVCB (log P >4) to accumulate in individuals that are frequently exposed (e.g. daily at work) to these substances. Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance (Rozman and Klaassen, 1996).
Conclusion
Oral uptake is expected based on information from the available studies and favourable physico chemical parameters. For dermal absorption low to moderate dermal absorption of at least a part of its constituents is to be expected based on information from available studies, and physicochemical parameters . Relatively wide distribution and excretion through urine is expected based on water solubility ranges and low molecular weights. The absorption values to be used for hazard assessment are therefore taken as 100% for the inhalation route, 90% for the oral route and 50% for the dermal route.
References:
Diliberto JJ, Usha G, Birnbaum LS (1988) Disposition of Citral in male Fischer rats. Drug Metab. Dispos. 16, 721-727
Hayes AJ, Markovic B (2003) Toxicity of Australian essential oil Backhousia citriodora (lemon myrtle). Part 2: Absorption and histopathology following application to human skin. Food Chem Toxicol 41: 1409-1416
Renwick AG (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes, A.W. (ed.) Principles and Methods of Toxicology. Raven Press, New York, USA, pp.103.
Rozman KK and Klaassen CD (1996) Absorption, Distribution, and Excretion of Toxicants. In: Klaassen CD (Ed.) Cassarett and Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill, New York, USA.
Scolnik M, Konichezky M, Tykochinsky G, Servadio C, Abramovici A (1994) Immediate vasoactive effect of Citral on the adolescent rat ventral prostrate. Prostrate 25: 1-9
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