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Description of key information

Oral uptake expected based on information from available studies (acute and repeated dose oral toxicity) and favourable physico chemical parameters. Dermal absorption expected based on information from available studies (irritation, sensitisation, acute dermal toxicity) and favourable physicochemical parameters. Relatively wide distribution and excretion through urine expected based on 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 3.99% for the dermal route.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
3.99
Absorption rate - inhalation (%):
100

Additional information

Toxicokinetic evaluation Eucalyptus citriodora 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

Eucalyptus citriodora 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, Eucalyptus citriodora 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

0.00%

1.00%

1,(+)-Citronellal

(R)-3,7-dimethyloct-6-enal

2385-77-5

219-194-5

70.00%

85.00%

 1,β-(+)-Citronellol

(R)-3,7-dimethyloct-6-en-1-ol

1117-61-9

214-250-5

1.00%

12.00%

Methyl Heptenone

6-methylhept-5-en-2-one

110-93-0

203-816-7

0.00%

4%

1,(-)-linalol

(R)-3,7-dimethyl-1,6-octadien-3-ol

126-91-0

204-811-2

0.00%

1.00%

Caryophyllene beta

Carylophyllene

87-44-5

201-746-1

0.00%

2.00%

1S,5S-(-)-alpha-Pinene

pin-2(3)-ene

7785-26-4

201-291-9

0.00%

3.00%

Myrcene beta

123-35-3

204-622-5

0.00%

1.00%

(Z/cis)-beta-Ocimene

 (Z)-3,7-dimethylocta-1,3,6,-triene

3338-55-4

222-081-3

0.00%

1.00%

1,(-)-isopulegol

Isopulegol

89-79-2

201-940-6

3.00%

15.00%

1,(-) neo-isopulegol

Neo isopulegol

96612-21-4

-

0.00%

7.00%

Citronellyl acetate

Citronellyl acetate

150-84-5

205-775-0

0.00%

4.00%

Terpinolene

p-mentha-1,4(8)-diene

586-62-9

209-578-0

0.00%

1.00%

Unknown and other minor constituents

-

-

0.00%

10.00%

The main constituent is 1,(+)-Citronellal , which adds up to a percentage range of (70-85%), and can therefore be considered representative of the whole substance.

ADME data

Absorption, distribution, metabolism and excretion data on Eucalyptus citriodora itself are not available and therefore the toxicokinetic assessment is based on the available toxicology data for Eucalyptus citriodora, as well as data for the main constituent Citronellal. 

Information from physico chemical and toxicity studies

An overview of the relevant physicochemical parameters for Eucalyptus citriodora and its major constituent 1,(+)-Citronellal is provided below:

 

Eucalyptus citriodora

1,(+)-Citronellal

 

 

From REACH dossier (CAS# 2385-77-5)

Physical state

Liquid

Liquid

Structure

UVCB

Molecular weight

UVCB

154 g/mol

Particle size

Not relevant

Not relevant

Water solubility

0.5 – 4364 mg/l at 25 °C

52 mg/L at 25 °C

Log Kow

2.06 – 6.3

3.83 at 25 °C

Surface tension

No data

No data

Vapour pressure

44.7 Pa at 25 °C

33.9 Pa at 25 °C

 

Absorption

Oral: Based on the relatively low molecular weight of the major constituent 1,(+)-Citronellal, absorption via the oral tract could be expected. Water solubility of the major constituent 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 Citronellal. 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 reportedmortality in two males and one female rat (30% mortality rate) following oral administration of 5000 mg/kg bw of Eucalyptus citriodora. Furthermore, in an OECD TG 422 study systemic effects such as nephropathy in male rats (hyaline droplet accumulation), and a reduction in the number of corpora lutea in females, were observed in an oral repeated dose toxicity study. These findings confirm that systemic absorption of the substance via the gastrointestinal tract takes place.

Dermal:An acute dermal toxicity test was performed on rabbits withEucalyptus citriodora. The skin of half of the animals (2M:1F) was abraded, making penetration more likely. Mortality was observed starting from the 1000 mg/kg bw dose group (1 animal). In the highest dose groups 3 animals of each group died. Clinical signs were only noted and included slight and severe depression. Furthermore, effects on some internal organs (liver and lungs discoloured, kidneys pitted, liver lesions) were observed, indicating systemic effects of dermal exposure.The skin irritating properties(blanching, reddening, swelling, scab formation)suggest that dermal penetration can be expected as the skin will be damaged and can therefore be easier penetrated. 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

MW

temp

VP (Pa)

water solubility (mg/l)

Log Kow

Density (g/ml)

Melting point

Max skin adherence (mg/cm2)

Dermal fraction absorbed 8 hours

(R)-3,7-dimethyloct-6-enal

2385-77-5

76.00%

154.35

25

33.9

514.22

3.53

0.8

25

8

0.196%

(R)-3,7-dimethyloct-6-en-1-ol

1117-61-9

4.70%

156.27

25

2.26

472.85

3.56

0.8

-12.16

8

0.193%

Carylophyllene

87-44-5

1.04%

204.352

25

4.16

0.54268

6.3

0.9075

25

9.075

1.390%

pin-2(3)-ene

7785-26-4

2.43%

136.234

25

534.66

4.071

4.48

0.859

-64

8.59

0.031%

Isopulegol

89-79-2

4.62%

154.249

25

0.662

943.2

3.37

0.911

78

9.11

1.090%

Neo isopulegol

96612-21-4

1.16%

154.249

25

0.662

943.2

3.37

0.911

78

9.11

1.090%

Unknown and other minor constituents

-

7.94%

Sum

100%

3.990%

The summed permeability calculated using the IH Skinperm tool was 3.99%. This is a conservative estimate of the skin absorption value for this UVCB and will be used for risk assessment.

 

Inhalation: Exposure via inhalation is not expected to a large extent due to the low vapour pressure. However, based on the log Kow values and molecular weights,as well as the potential for absorption following ingestion would favour absorption directly across the respiratory tract epithelium.

Distribution

Distribution of Eucalyptus citriodora and 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 toxicity and target organs suggest that the substance is distributed to the liver, kidney as well as female reproductive system (ovaries).

Metabolism

No information on metabolism can be derived from the physicochemical data that is available for Eucalyptus citriodora. No information on metabolism is available from studies, but the UVCB substance Eucalyptus citriodora is expected be transformed to its major constituent 1,(+)-Citronellal. This substance has 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 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.

Elimination

Based on the relatively low molecular weight and high water solubility, the substance and its major constituent Citronellal tend to be excreted via the urine via passive diffusion. Re-absorption from urine into systemic circulation would also be possible. Secretion via bile and as a consequence faeces is not likely. Excretion via breast milk, saliva and sweat is also not expected to a large extent as the substance is not regarded lipophilic (Log Kow < 4).

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

 

Eucalyptus citriodora

Skin irritation / corrosivity

Blanching, reddening, swelling, scab formation (Skin Irrit. 2)

Dermal toxicity data

Mortality and effects on internal organs observed (acute toxicity)

Oral toxicity data

Only mortality, but no effects of internal organs observed (acute toxicity)

Skin sensitisation data

Skin Sens. 1, since the major constituent 1,(+)-Citronellal (CAS 2385-77-5) is currently classified as skin sensitiser.

Target organs

Nephropathy in male rats (hyaline droplet accumulation), and a reduction in the number of corpora lutea in females.


Conclusion

Oral uptake expected based on information from available studies (acute and repeated dose oral toxicity) and favourable physico chemical parameters. Dermal absorption expected based on information from available studies (irritation, sensitisation, acute dermal toxicity) and favourable physicochemical parameters. Relatively wide distribution and excretion through urine expected based on 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 3.99% 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).

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