Cymbopogon winterianus, ext.

Endpoint summary

Description of key information

Oral uptake is expected based on information from available studies (acute and repeated dose oral toxicity) and favourable physicochemical parameters. Dermal absorption is also expected based on information from available studies (sensitisation, modelling) and favourable physicochemical parameters. In addition, uptake via the inhalation route cannot be excluded. Relatively wide distribution and excretion through urine is expected based on the metabolism described for the major constituents and their high water solubility and low molecular weight. The absorption values to be used for hazard assessment are 100% for the inhalation route, 50% for the oral route and 1.996% for the dermal route.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

1.996

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic evaluation of Cymbopogon winterianus 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

Citronella oil (Cymbopogon winterianus) 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, Citronella oil is part of the particular category of essential oils, extracts, fractions and distillation products of the Rutaceae family, and consists of the following identified constituents:

 

	Name - Constituent	CAS Number - Constituent	EC Number - Constituent	Concentration range
1,L-Limonene	(S)-p-mentha-1,8-diene	5989-54-8	227-815-6	1.50%	5.00%
1,(+)-Citronellal	(R)-3,7-dimethyloct-6-enal	2385-77-5	219-194-5	7.00%	43.00%
Geraniol	Geraniol (E-isomer)	106-24-1	203-377-1	19.00%	49%
(±)-β-Citronellol: mixture	3,7-Dimethyl-6-octen-1-ol	106-22-9	203-375-0	8.00%	14.00%
Geranyl acetate (E-isomer)	trans-3,7-Dimethyl-2,6-octadien-1-yl acetate	105-87-3	203-341-5	2.00%	5.00%
Camphene	Mixture of isomers	79-92-5	201-234-8	0.00%	<1%
Linalool	(±)​-​3,7-​Dimethyl-​3-​hydroxy-​1,6-​octadiene	78-70-6	201-134-4	0.00%	2.00%
Caryophyllene beta	trans-(1R,9S)​-​8-​Methylene-​4,11,11-​trimethylbicyclo[7.2.0]​undec-​4-​ene	87-44-5	201-746-1	0.00%	3.50%
Sabinene (mixture of isomers)	thuj-4(10)-ene	3387-41-5	222-212-4	0.00%	<1 %
Myrcene beta	7-Methyl-3-methylene-1,6-octadiene	123-35-3	204-622-5	0.00%	<1%
beta-ocimene (cis & trans): mixture of isomers	(Z)-3,7-dimethylocta-1,3,6,-triene (cis) / (E)-3,7-dimethylocta-1,3,6-triene (trans)	3338-55-4 (cis) / 3779-61-1 (trans)	222-081-3	0.00%	<1%
Isopulegol	(1R,3R,4S)-p-Menth-8-en-3-ol or (−)-Isopulegol	89-79-2	201-940-6	0.00%	2.00%
Neo isopulegol	(-)-Neo Isopulegol	96612-21-4		0.50%	3.00%
Citronellyl acetate	Mixture of isomers	150-84-5	205-775-0	1.00%	4.00%
Cadinenes	Mixture of isomers Alpha, Gamma, Delta	483-76-1 / 39029-41-9 / 24406-05-1		1.00%	4.00%
Terpineol	mixture of 3 isomers: alpha, beta and gamma	8000-41-7	232-268-1	0.00%	<1%
(+/-)-Borneol	endo-(1R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-ol	507-70-0	208-080-0	0%	<1%
Alpha-pinene	2,6,6-Trimethylbicyclo[3.1.1]hept-2-ene	80-56-8	201-291-9	0%	<1%
(−)-β -Elemene (beta)	Cyclohexane, 1-ethenyl-1-methyl-2,4-bis(1-methylethenyl)-, (1S,2S,4R)-	515-13-9	610-676-4	0%	3.00%
(-)-Elemol	(1S,2S,4R)-(-)-α,α-dimethyl-1-vinyl-o-menth-8-ene-4-methanol	639-99-6	211-360-5	0.50%	5.00%
(-)-Germacrene D	1,6-Cyclodecadiene, 1-methyl-5-methylene-8-(1- methylethyl)-, [S-(E,E)]-	23986-74-5		0.50%	3.00%
Eugenol	2-Methoxy-4-(2-propenyl)phenol	97-53-0	202-589-1	0%	3.00%
Geranial	trans-isomer of 3,7-Dimethylocta-2,6-dienal	141-27-5	205-476-5	0%	11.00%
Muurolol (T & A)	tau-muurolol, alpha-muurolol	19912-62-0 / 19435-97-3		0%	3.00%
Nerol	cis-3,7-Dimethyl-2,6-octadien-1-ol	106-25-2	203-378-7	0%	<1%
Terpinolene	p-mentha-1,4(8)-diene	586-62-9	209-578-0	0%	<1%
Decanal	1-decylaldehyde	112-31-2	203-957-4	0%	<1%
Farnesol	2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol	4602-84-0	225-004-1	0%	<1%
p-mentha-1(7),2-diene	(+/-)-beta-Phellandrene	555-10-2	209-081-9	0%	<1%
Neryl acetate	cis-3,7-Dimethyl-2,6-octadien-1-yl acetate	141-12-8	205-459-2	0%	1.00%
P-cymene	1-Isopropyl-4-methylbenzene	99-87-6	202-796-7	0%	<1.00%
Unknown and other minor constituents <1%				0%	<10.00%

 

The main constituents of Cymbopogon winterianus are 1,(+)-Citronellal, Geraniol,(±)-β-Citronellol, which add up to an percentage range of 34-106% (typical concentration 70.7%).

 

ADME data

Absorption, distribution, metabolism and excretion data onCymbopogon winterianusitself are not available and therefore the toxicokinetic assessment is based on the available toxicology data forCymbopogon winterianus, as well as data for the main constituents. 

 

Information from physico chemical and toxicity studies

An overview of the relevant physicochemical parameters for Cymbopogon winterianus and its major constituents 1,(+)-Citronellal, Geraniol and (±)-β-Citronellol, is provided below:

	Citronella oil	1,(+)-Citronellal	Geraniol	Citronellol
		From REACH dossier (CAS# 2385-77-5)	From REACH dossier (CAS# 106-24-1)	From REACH dossier (CAS# 106-22-9)
Physical state	Liquid	Liquid	Liquid	Liquid
Structure	UVCB
Molecular weight	UVCB	154 g/mol	154 g/mol	156 g/mol
Water solubility	0.05 - 1767 mg/l at 25 °C	52 mg/L at 25 °C	100 mg/L at 25 °C	307 mg/L at 25 °C
Log Kow	2.73 - 7.04	3.83 at 25 °C	2.6 at 25 °C	3.41 at 25 °C
Vapour pressure	22.14 Pa at 25 °C	33.9 Pa at 25 °C	0.00796 Pa at 20 °C	8.6 Pa at 20 °C

 

Absorption

Oral: Based on the relatively low molecular weight of the major constituents 1,(+)-Citronellal, Geraniol and (±)-β-Citronellol absorption via the oral tract could be expected. Water solubility of the major constituents (52-307 mg/L) is regarded high enough to expect ready dissolution in gastrointestinal fluids. Furthermore uptake by passive diffusion can be expected based on the moderate log Kow values of the major constituents. Uptake throughaqueous pores or carriage of such molecules across membranes with the bulk passage of waterin the GI tract can be expected based on the relatively low molecular weight. 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 could be absorbed in the human body via the oral route. This is supported by the findings in an oral acute toxicity study, which reported severe toxic effects following oral administration of 5000 mg/kg bw of Cymbopogon winterianus to a female rat. Furthermore, in an OECD TG 422 feeding study, a reduction in litter size and fluctuations in some biochemical parameters were observed. These findings are supportive for systemic absorption of the substance via the gastrointestinal tract.

Dermal: An acute dermal toxicity test was performed on rabbits with Cymbopogon winterianus (single dose occluded dressing, 24h exposure). Treatment with the test item did not result in any deaths, clinical signs of toxicity or macroscopical abnormalities, indicating the absence of systemic effects of dermal exposure.Furthermore, the substance did not cause any skin irritant effects up to the limit dose. However, as sensitisation is also expected for this substance, some uptake must occur, although this may only be applicable for a small fraction.

 

Due to the liquid state of the substance, dermal absorption can be expected. In order to assess the potential for dermal absorption, the absorption of all components with a typical concentration of 1% or higher was calculated using the IH Skinperm tool version 2.0. In the model the following input was used as a worst-case, which resulted in the highest dermal absorption:

-         Instantaneous deposition: 100 mg;

-         Affected skin area: 1,000 cm2;

-         Maximum skin adherence: 7 mg/cm2;

-         Thickness of stagnant air: 100 cm;

-         Weight fraction: 1;

-         Observation time: 24 hours;

-         Calculated intervals: 10,000.

The substance specific input for Skinperm was taken from the QPRF document and Substance Identity Profile. Missing information was taken from reliable sources such as the ECHA substance database, the Gestis substance database, Dohsbase or Chemspider. The following input was used.

 

Name	CAS	Typical concentration (%)	Molecular weight	Vapour pressure (Pa)	water solubility (mg/l)	Log Kow	Density (g/ml)	Melting point	Max skin adherence (mg/cm2)	Dermal fraction absorbed 8 hours
(R)-p-mentha-1,8-diene	5989-27-5	3.76%	136.234	193	44.388	4.83	0.842	-74	8.42	0.020%
Citronellal	2385-77-5	36.37%	154.35	33.9	514.22	3.53	0.851	25	8.51	0.191%
Geraniol	106-24-1	21.56%	154.249	2.12	1012.6	3.47	0.8894	-15	8.894	0.250%
Citronellol	106-22-9	12.74%	156.27	2.26	472.85	3.56	0.858	-20	8.58	0.136%
Geranyl acetate	105-87-3	3.10%	196.29	6.17	57.985	4.48	0.91	-6.1	9.1	0.013%
Isopulegol	89-79-2	1.07%	154.249	0.662	943.2	3.37	0.911	78	9.11	0.012%
Neo isopulegol	96612-21-4	1.75%	154.249	0.662	943.2	3.37	0.911	78	9.11	0.019%
Citronellyl acetate	150-84-5	2.62%	198.31	7.01	27.004	4.56	0.891	-7.4	8.91	0.010%
Cadinenes	483-76-1 / 39029-41-9 / 24406-05-1	2.18%	204.352	2.51	0.80763	6.32	0.916	35.55	9.16	0.037%
Cyclohexane, 1-ethenyl-1-methyl-2,4-bis(1-methylethenyl)-, (1S,2S,4R)-	515-13-9	2.03%	204.36	12.3	0.27444	7.04	0.862	-0.48	8.62	0.015%
(1S,2S,4R)-(-)-α,α-dimethyl-1-vinyl-o-menth-8-ene-4-methanol	639-99-6	2.70%	222.37	10.501	0.0514	5.54	0.945	50.56	9.45	0.004%
Germacrene D	23986-74-5	2.18%	204.351	3.04	0.81945	6.99	0.9	15.76	9	0.061%
Eugenol	97-53-0	1.05%	164.201	1.26	979.83	2.73	1.0652	-7.5	10.652	0.012%
Muurolol (T & A)	19912-62-0 / 19435-97-3	3.00%	222.366	0.011	14,739	4.77	0.937	81	9.37	1.137%
Unknown and other minor constituents		3.89%
Sum		100%								1.996%

The weighted permeability calculated using the IH Skinperm tool was 1.996% and this will be used for risk assessment. This number is corrected for the unknown and minor constituents not taken into account in the Skinperm modelling.

 

Inhalation: The moderate log Kow values of the main constituents (between -1 and 4) as well as their molecular weights are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The constituents with a higher log Kow (>4), and a low water solubility (<1 mg/L) may be taken up by micellular solubilisation. These physico-chemical propertieswould also favour absorption directly across the respiratory tract epithelium following aspiration.

Distribution

Distribution ofCymbopogon winterianusand its major constituent is expected based on the relatively low molecular weights. Also the water solubility favours distribution through the body, while the Log Kow suggests distribution into cells. A higher intracellular concentration is expected, especially in fatty tissues. Signs of liver discolouration in after acute exposure, and reproductive toxicity after repeated exposure, suggests that the substance is distributed to the liver and (female) reproductive system.

 

Metabolism

No information on metabolism can be derived from the physicochemical data that is available forCymbopogon winterianus. No information on metabolism of this UVCB is available from studies, but data is available for some of its major constituents 1,(+)-Citronellal, Geraniol.

1,(+)-Citronellalhas been investigated in rabbits. In a study by Ishida et al. (1989) regioselective oxidation was found and a trans-positioned methyl group was carboxylated in the metabolites detected in the urine of rabbits dosed orally with 2g test substance[1]. The formation of metabolites occurred via both oxidation and reduction pathways. An earlier study by Kühn et al (1938) reported urinary excretion of menthoglycol-glucuronic acid by rabbits after feeding of citronellal[2], suggesting the involvement of phase-II glucuronidation processes.

ForGeraniolseveral studies have been performed. Chadha et al. (1984) investigated the metabolic pathway of Geraniol in rats that were repeatedly exposed to 800 mg/kg bw by gavage[3]. Two metabolism pathways were identified including; 1) oxidation to geranic acid with subsequent hydration to 3-hydroxy citronellic acid, 2) selective omega-oxidation of the C8-methyl to yield 8-hydroxygeraniol and 8 -carboxygeraniol, which further oxidized to the principal urinary metabolite 2,6-dimethyl-2,6-octadienedioic acid. The detoxification of geraniol was also described by Williams et al. (1959)[4]. Following hydrolysis, geraniol undergoes a complex pattern of alcohol oxidation, ω-oxidation, hydration, selective hydrogenation and subsequent conjugation to form oxygenated polar urinary metabolite. Alternatively, the corresponding carboxylic acids formed can enter the beta-oxidation pathway and are metabolized to carbon dioxide.

 

Elimination

Based on the relatively low molecular weight and high water solubility, the substance and its major constituents are expected to be excreted via the urine via passive diffusion. Re-absorption from urine into systemic circulation would also be possible. Secretion via bile and thus faeces is unlikely. Metabolites of the major constituents are also mainly excreted though the urine, as described in the section on metabolism. Excretion of the main constituents via breast milk, saliva and sweat is not expected to a large extent as these constituents are not regarded as lipophilic (Log Kow < 4), however (partial) excretion of some of the other constituents with a log Kow > 4 cannot be excluded.

 

Accumulation

The substance cannot be regarded as highly lipophilic based on its Log Kow and is therefore not expected to have a high accumulation potential.

 

Data from other studies

	Cymbopogon winterianus
Oral toxicity data	Moribound state and patchy pallor of the liver as well as epithelial sloughing of the gastric mucosa.
Dermal toxicity data	Treatment with the test item did not result in any deaths, clinical signs of toxicity or macroscopical abnormalities.
Skin irritation / corrosivity	No skin irritation observed in dermal toxicity test
Skin sensitisation data	Skin Sens. 1, since the major constituents 1,(+)-citronellal (CAS 2385-77-5), citronellol (CAS 1117-61-9) and geraniol (CAS 106-24-1) are currently classified as skin sensitisers.
Target organs	Signs of liver discolouration in after acute exposure, and reproductive toxicity after repeated exposure, suggests that the substance is distributed to the liver and (female) reproductive system.

 

Conclusion

Oral uptake is expected based on information from available studies (acute and repeated dose oral toxicity) and favourable physicochemical parameters. Dermal absorption is also expected based on information from available studies (sensitisation, modelling) and favourable physicochemical parameters. In addition, uptake via the inhalation route cannot be excluded. Relatively wide distribution and excretion through urine is expected based on the metabolism described for the major constituents and their high water solubility and low molecular weight. The absorption values to be used for hazard assessment are 100% for the inhalation route, 50% for the oral route and 1.996% for the dermal route.

[1]Terpenoid biotransformation in mammals. V. Metabolism of (+)-citronellal, (±)-7-hydroxycitronellal, citral, (−)-perillaldehyde, (−)-myrtenal, cuminaldehyde, thujone, and (±)-carvone in rabbits, T. Ishida, M. Toyota & Y. Asakawa, Xenobiotica Vol. 19 , Iss. 8,1989

[2]Über die Ausscheidung: von Menthoglykol-glucuronsäure durch Kaninchen nach Fütterung von Citronellal. Kühn, R. & Löw., I. Hoppe-Seyler´s Zeitschrift für physiologische Chemie, 254(3-6), pp. 139-143. (1938).

[3]Metabolism of Geraniol and Linalool in the Rat and effects on liver and Lung Microsomal Enzymes. Chadha A, Madyastha M, Xenobiotica 14: 365-374, 1984

[4]The Metabolism and Detoxification of Drugs, Toxic Substances and Other Organic Compounds. 2nd Ed., Chapman and Hall Ltd., London, p. 520. Williams RT(1959)