Ylang-ylang, ext.

Endpoint summary

Description of key information

Oral uptake is expected based on information from the available studies (acute and repeated dose oral toxicity) and the favourable physico chemical parameters. Dermal absorption would be possible based on information from available studies (sensitisation) and physicochemical parameters. Relatively wide distribution and excretion through urine is expected based on low/moderate water solubility and low molecular weights. The absorption values to be used for hazard assessment are therefore taken as 100% for the inhalation route, 50% for the oral route and 7.47 % for the dermal route.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

7.47

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic evaluation of Ylang Ylang Ext/I/II (CAS: 83863-30-3 / EC 281-092-1) 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

Ylang Ylang Ext/I/II 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, the essential oil of Ylang Ylang Ext/I/II obtained from the flowers of Cananga odorata (Annonaceae) by steam distillation.

 

Table 1 Ylang Ylang Ext/I/II constituents

Name-Constituent	CAS Number-Constituent	EC Number-Constituent	Concentration range % (typical)
Germacrene D	23986-74-5	-	5.00-28.00 %
Linalool	78-70-6	201-134-4	2.00-24.00 %
2,6,10-Trimethyldodeca-2,6,9,11-tetraene /Farnesene	502-61-4 / 26560-14-5	207-948-6	1.00-21.00 %
Benzyl acetate	140-11-4	205-399-7	0.20 -20.00 %
Caryophyllene beta	87-44-5	201-746-1	2.00-18.00 %
4-Methylanisole	104-93-8	203-253-7	1.00-16.00 %
Geranyl acetate	105-87-3	203-341-5	1.70 -15.00 %
Benzyl benzoate	120-51-4	204-402-9	3.00-10.00 %
Methyl benzoate	93-58-3	-	0.20-9.00 %
Cinnamyl acetate	103-54-8	203-121-9	0.20-6.50 %
Benzyl salicylate	118-58-1	204-262-9	1.00-4.00 %
3,7,11-Trimethyldodeca-2,6,10-trienyl acetate/ Farnesyl acetate	29548-30-9	249-689-1	0.50-4.50 %
Farnesol	4602-84-0	225-004-1	0.10-4.00 %
Geraniol	106-24-1	203-377-1	0.10-3.00 %
Prenyl acetate	1191-16-8	214-730-4	0.10-3.20 %
Other minor constituent and unspecified compounds			5.00-15.00 %

ADME data

Absorption, distribution, metabolism and excretion data onYlang Ylang Oil Ext/I/IIitself are not available and therefore the toxicokinetic assessment is based on the available toxicology data for the main constituents of theUVCB (typical around 60 %).   

Information from physico chemical and toxicity studies

An overview of the relevant physicochemical parameters forYlang Ylang Oil Ext/I/IIis provided below:

 

Table 2 physicochemical parameters

	Ylang Ylang Oil Ext/I/II
Physical state	Liquid
Structure	UVCB
Molecular weights	122.164-264.403 g/mol
Log Kow	>= 4.0
Water solubility (mg/l)	0.43-5043.40 mg/L at 25°C
Vapour pressure	22.23 Pa at 25°C

 

Absorption

Oral: As the molecular weight range of this UVCB is below 300, 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 unlikely based on the log Kow value of Ylang Ylang ext/I/II. 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 the repeated dose toxicity study where liver and kidney effects were observed at 718 mg/kg bw, and increased liver weights and kidney weights were found in mice following repeated dose administration, these findings confirm that systemic absorption of the substance via the gastrointestinal tract can take place.

Dermal: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). In a dermal toxicity study no acute dermal toxicity was observed in rabbits exposed to 5000 mg/kg bw. Furthermore, even though Ylang Ylang Ext/I/II is not a corrosive, the skin irritating properties observed in the read across in vivo skin irritation test suggest that this UVCB may damage the skin and thereby increase its penetrating potential (see read-across justification for rerference). As this UVCB is considered sensitising, some uptake must occur, although this may only be applicable for specific constituents.

In order to assess the potential for dermal absorption, the absorption of all components in this UVCB 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: 10 cm;

-         Weight fraction: 1;

-         Observation time: up to maximum dermal absorption (taking evaporation into account)

-         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:

 

Table 3 Input Skinperm

Name	CAS	Typical conc. (% w/w)	MW	Vapour pressure (Pa)	Water solubility (mg/L)	Log Kow	Density (g/mL)	Melting point	Max skin adherence (mg/cm^2)	Dermal fraction absorbed %
4-Methylanisole	104-93-8	8.50%	122.167	160	293.93	2.62	0.969	-32	9.69	0.004%
Linalool	78-70-6	11.50%	154.253	11.1	709.26	3.38	3.38	0	33.8	4.036%
Benzyl acetate	140-11-4	9.00%	150.177	25	839.48	2.08	1.054	-51	10.54	0.010%
Geranyl acetate	105-87-3	7.00%	196.29	6.17	57.985	4.48	4.48	0.91	44.8	0.033%
Cinnamyl acetate	103-54-8	2.50%	176.215	1.62	183.76	2.85	1.057	15	10.57	0.021%
Caryophyllene beta	87-44-5	8.00%	204.357	4.16	0.54268	6.3	0.9075	25	9.075	0.116%
Germacrene D	23986-74-5	17.00%	204.357	3.04	0.81945	6.99	0.9	15.76	9	0.517%
Farnesene	502-61-4	10.00%	204.357	3.33	0.42892	7.1	0.857	-17.2	8.57	0.283%
Farnesol	4602-84-0	1.50%	222.372	0.00525	10.958	5.77	0.886	3.24	8.86	0.690%
Benzyl benzoate	120-51-4	6.00%	212.248	0.0741	20.002	3.54	1.118	21	11.18	0.645%
Farnesyl acetate	29548-30-9	2.00%	264.409	0.0652	0.58639	6.77	0.91	7.27	9.1	0.551%
Benzyl salicylate	118-58-1	2.50%	228.247	0.0024	23.419	4.31	1.17	19	11.7	0.501%
Geraniol	106-24-1	1.25%	154.253	2.12	1012.6	3.47	3.47	0.8894	34.7	0.060%
Prenyl acetate	1191-16-8	1.00%	128.171	556	5043.4	2.18	0.92	-53.9	9.2	0.000%
Methyl benzoate	93-58-3	4.00%	136.15	50.6	3493.6	1.83	1.094	-12	10.94	0.003%

 

The sum of the weighted permeability calculated using the IH Skinperm tool was 7.47 % 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 lipophilicity of the main constituents (log Kow >4), and a low water solubility indicate that uptake via the lungs may be mainly via micellular 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 Ylang Ylang Ext/I/II and its major constituents is expected based on the relatively low molecular weights. Also distribution throughout the body would be possible due to the wide water solubility ranges. As the higher Log Kow range suggests the possibility for distribution into cells, a higher intracellular concentration is expected, especially in fatty tissues. Signs of toxicity and target organs suggest that the substance is at least distributed to the liver and kidney.

Metabolism

No information on metabolism can be derived from the physicochemical data that is available for Ylang Ylang Ext/I/II. Also, no information on metabolism of the UVCB is available from specific studies. However, one of the main constituents; Caryophyllene beta is known to have an (inhibitory) effect on CYP3A Cytochrome p450 enzyme activities[1]. Hepatic phase 1 metabolism mediated by P450 enzymes may therefore an important first step in the metabolic pathway for this UVCB.

 

Elimination

Based on the male-rat specific renal effects observed in the OECD TG 422 study, excretion is expected to take place via the kidney. This is supported by the relatively low molecular weights of the constituents. Excretion via bile is not likely, as in the rat it has been found that substances with molecular weights below around 300 do not tend to be excreted into the bile (Renwick, 1994)[2]. 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)^[3].

 

Key information from Reach dossier relevant for toxicokinetic assessment

Table 4 Overview

	Ylang Ylang Ext/I/II
Skin irritation / corrosivity	Ylang Ylang Ext/I/II is an irritant to skin.
Oral toxicity data	Coma and chromodacryorrhea were observed at 5000 mg/kg bw
Dermal toxicity data	No mortality or clinical signs of toxicity.
Skin sensitisation data	Classified for skin sensitization (Skin Sens. 1B / H317)
Repeated dose toxicity	Liver and kidney effects were observed following repeated dose administration.

Conclusion

Oral uptake is expected based on information from the available studies (acute and repeated dose oral toxicity) and the favourable physico chemical parameters. Dermal absorption would be possible based on information from available studies (sensitisation) and physicochemical parameters. Relatively wide distribution and excretion through urine is expected based on low/moderate water solubility and low molecular weights. The absorption values to be used for hazard assessment are therefore taken as 100% for the inhalation route, 50% for the oral route and 7.47 % for the dermal route.

References

1.     Nguyen LT . The inhibitory effects of β-caryophyllene, β-caryophyllene oxide and α-humulene on the activities of the main drug-metabolizing enzymes in rat and human liver in vitro. Chem Biol Interact. 2017 Dec 25; 278: 123-128. Epub 2017 Oct 23.

2.     Renwick AG (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes,A.W. (ed.) Principles and Methods of Toxicology. Raven Press, New York, USA, pp.103.

3.     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