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Description of key information

Toxicokinetic evaluation of Ylang Ylang Oil III(CAS #)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 Oil III 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 III is obtained from the flowers of Cananga odorata (Annonaceae) by steam distillation.

Table 1. Ylang Ylang III oil constituents

Name-Constituent

CAS Number-Constituent

EC Number-Constituent

Concentration

range %

4-Methylanisole

104-93-8

203-253-7

0.10 -1.40 %

Geraniol

106-24-1

203-377-1

0.10 - 0.80 %

Linalool

78-70-6

201-134-4

0.10 - 4.00 %

Benzyl acetate

140-11-4

205-399-7

0.10 -3.00 %

Methyl benzoate

93-58-3

202-259-7

0.10 - 0.90 %

Geranyl acetate

105-87-3

203-341-5

0.40 - 6.60 %

Prenyl acetate

1191-16-8

214-730-4

0.01 - 0.20 %

Cinnamyl acetate

103-54-8

203-121-9

0.10 - 2.50 %

Caryophyllene beta

87-44-5

201-746-1

5.00 - 20.00 %

Germacrene D

23986-74-5

639-624-9

15.00 - 35.00 %

2,6,10-Trimethyldodeca-2,6,9,11-tetraene /Farnesene

502-61-4 / 26560-14-5

207-948-6

9.00 - 29.00 %

Farnesol

4602-84-0

225-004-1

0.20 - 4.00 %

Benzyl benzoate

120-51-4

204-402-9

2.00 - 8.50 %

3,7,11-Trimethyldodeca-2,6,10-trienyl acetate/ Farnesyl acetate

29548-30-9

249-689-1

1.00 - 6.00 %

Benzyl salicylate

118-58-1

204-262-9

1.00- 5.00 %

Cadinenes delta

483-76-1

-

0.00 - 6.00 %

Cadinol alpha

481-34-5

-

0.00 - 3.00 %

alpha-Copaene

3856-25-5

223-364-4

0.00 - 3.00 %

Humulene alpha

6753-98-6

229-816-7

1.00 - 7.00 %

gamma-Muurolene

30021-74-0

-

0.00 - 3.00 %

ADME data

Absorption, distribution, metabolism and excretion data on Ylang Ylang III oil itself are not available and therefore the toxicokinetic assessment is based on the available toxicology data forYlang Ylang III oil, as well as data for the main constituents Caryophyllene beta, Germacrene D, 2,6,10-Trimethyldodeca-2,6,9,11-tetraene/Farnesene which can make up 29-84% of this UVCB (typical around 60%)

Information from physico chemical and toxicity studies

An overview of the relevant physicochemical parameters for Ylang Ylang III oil is provided below:

Table 2. Physicochemical parameters

 

 

Main constituents

 

Ylang Ylang III oil

Caryophyllene beta

Germacrene D

Farnesene

Physical state

Liquid

Liquid

Liquid

Liquid

Structure

UVCB

Molecular weights

122.17 - 264.4 g/mol

204.4 g/mol

204.4 g/mol

204.4 g/mol

Log Kow

1.83-7.10

6.3

6.99

7.1

Water solubility (mg/l)

0.043 - 5043.4 mg/L at 25°C.

0.54268 mg/L at 25°C.

3.04 mg/L at 25°C.

3.33 mg/L at 25°C.

Vapour pressure

3.31 Pa at 25°C.

4.16 Pa at 25°C

0.81945 mg/L at 25°C.

0.42892 mg/L 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 likely based on the moderate log Kow values of Ylang Ylang III oil. 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 oral acute toxicity and repeated dose toxicity read-across studies where coma and chromodacryorrhea were observed at 5000 mg/kg bw and liver effects were seen following repeated dose administration. As the source UVCB contained the same constituents (only difference in concentration ranges – refer to Read-Across justification document), these findings confirm that systemic absorption of the substance via the gastrointestinal tract can take place.

Dermal: Based on the physicochemical 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 read-across dermal toxicity study no acute dermal toxicity was observed in rabbits exposed to 5000 mg/kg bw (the source UVCB contained the same constituents, with only difference in concentration ranges – refer to Read-Across justification document). Furthermore, even thoughYlang Ylang Oil IIIis not a corrosive, the skin irritating propertiesobserved in the in vivo skin irritation test suggest that this UVCB may damage the skin and therebyincrease its penetrating potential. 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/cm2)

Dermal fraction absorbed %

4-Methylanisole

104-93-8

0.31%

122.16

160

293.93

2.62

0.969

-32

9.69

0.000%

Linalool

78-70-6

1.25%

154.25

11.1

709.26

3.38

3.38

0

33.8

0.454%

Benzyl acetate

140-11-4

0.60%

150.17

25

839.48

2.08

1.054

-51

10.54

0.001%

Geranyl acetate

105-87-3

2.60%

196.29

6.17

57.985

4.48

4.48

0.91

44.8

0.013%

Cinnamyl acetate

103-54-8

0.84%

176.21

1.62

183.76

2.85

1.057

15

10.57

0.007%

Caryophyllene beta

87-44-5

12.35%

204.35

4.16

0.54268

6.3

0.9075

25

9.075

0.185%

Germacrene D

23986-74-5

25.00%

204.35

3.04

0.81945

6.99

0.9

15.76

9

0.787%

Farnesene

502-61-4

21.00%

204.35

3.33

0.42892

7.1

0.857

-17.2

8.57

0.616%

Farnesol

4602-84-0

2.00%

222.37

0.00525

10.958

5.77

0.886

3.24

8.86

1.854%

Benzyl benzoate

120-51-4

6.00%

212.24

0.0741

20.002

3.54

1.118

21

11.18

0.668%

Farnesyl acetate

29548-30-9

3.00%

264.40

0.0652

0.58639

6.77

0.91

7.27

9.1

0.857%

Benzyl salicylate

118-58-1

2.50%

228.24

0.0024

23.419

4.31

1.17

19

11.7

0.010%

Geraniol

106-24-1

0.40%

154.25

2.12

1012.6

3.47

3.47

0.8894

34.7

0.020%

Prenyl acetate

1191-16-8

0.10%

128.17

556

5043.4

2.18

0.92

-53.9

9.2

0.000%

Methyl benzoate

93-58-3

0.50%

136.15

50.6

3493.6

1.83

1.094

-12

10.94

0.000%

Cadinenes Delta

483-76-1

3.50%

204.35

2.51

0.80763

6.32

0.9

35.55

9

0.068%

Cadinol Alpha

481-34-5

2.00%

222.36

0.011

14.739

4.77

0.9

69.58

9

0.650%

alpha copaene

3856-25-5

1.50%

204.35

6.35

0.030229

5.36

0.9

38.67

9

0.003%

Humulene alpha

6753-98-6

3.50%

204.35

2.04

1.5354

6.95

0.8

35.48

8

0.112%

gamma-Muurolene

30021-74-0

2.10%

204.35

4.82

0.3853

6.545

0.9

38

9

0.024%

The weighted permeability calculated using the IH Skinperm tool was 6.49% 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 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 physicochemical properties would also facilitate absorption directly across the respiratory tract epithelium following aspiration.

Distribution

Distribution of Ylang Ylang III oil 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 III oil. 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).

Table 4. Key information from REACH dossier relevant for toxicokinetic assessment

 

Ylang Ylang III oil

Skin irritation / corrosivity

Based on the results obtained, it can be concluded that Ylang Ylang III oil is an irritant to skin.

Oral toxicity data

Coma and chromodacryorrhea were observed at 5000 mg/kg bw

Dermal toxicity data

Treatment with the test item did not result in any deaths or clinical signs of toxicity.

Skin sensitisation data

Classified for skin sensitisation (Skin Sens. 1B / H317) (read across from Ylang Ylang I oil)

Repeated dose toxicity

Liver 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), physicochemical parameters and modelling of the skin permeability using the IH Skinperm tool. 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 6.49% 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.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
6.49
Absorption rate - inhalation (%):
100

Additional information