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See also attached document on Toxicokinetic assessment Cedarwood Texas oil - Terpenes

Toxicokinetic evaluation of Cedarwood Texas oil distilled Terpenes - Cedrene (Type 1) and Thujopsene (Type 2) 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

Cedarwood Texas oil distilled - Terpenes are substances 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 Cedarwood Texas obtained from the wood of Juniperus mexicana (Cupressaceae) by distillation.

Name-Constituent

CAS Number-Constituent

EC Number-Constituent

Concentration

range % Cedrene

Concentration

range % Thujopsene

Thujopsene

470-40-6

207-426-8

33-50

50-75

α-Cedrene

β-Cedrene

469-61-4

546-28-1

207-418-4

208-898-8

28-40

4-20

2-30

3-8

α-Chamigrene

β-Chamigrene

19912-83-5

18431-82-8

-

-

0.01-3

0.01-3

0-7

0-5

Cuparene

16982-00-6

241-061-5

0.01-6

1-7

Cedrol

77-53-2

201-035-6

0.01-3

0-14

α-Duprazianene

79801-29-9

-

0.01-3

0-3

α-Himachalene

β-Himachalene

3853-83-6

1461-03-6

-

-

0.01-3

0.01-3

0-3

-

β -Acoriadene

γ-Acoradiene

28477-64-7

28400-12-6

-

-

0-3

0-3

0-3

0-3

β -Caryophyllene

87-44-5

-

0-3

0-3

α -Funebrene

50894-66-1

-

0-3

-

Unknown constituents non-volatile fraction

-

-

0-5

0-10

Other minor and unknown volatile constituents

-

-

0-15

0-10

ADME data

Absorption, distribution, metabolism and excretion data on Cedarwood Texas Terpenes – Cedrene (Type 1) and Thujopsene (Type 2) itself are not available and therefore the toxicokinetic assessment is based on the available toxicology data for Cedarwood Texas Terpenes – Cedrene (Type 1) and Thujopsene (Type 2), as well as data for the main constituents

 

Information from physico chemical and toxicity studies

An overview of the relevant physicochemical parameters for Cedarwood Texas Terpenes – Cedrene (Type 1) and Thujopsene (Type 2) is provided below:

 

Cedarwood Texas Terpenes – Cedrene (Type 1) and Thujopsene (Type 2)

Physical state

Liquid

Structure

UVCB

Molecular weights

202.34 - 222.37 g/mol

Log Kow

Min. 4.33, Max. 7.04;100 % of the NCS has aLog Kow > 4

Water solubility (mg/l)

Min.0.03, Max. 8.72; 100 % of the NCS has a water solubility < 10 mg/L.

Boiling point (°C)

Min. 239.79, Max. 280.20

Vapour pressure

6.4 Pa at 25°C. The vapour pressure of the constituents ranges from Min. 0.0184 Max. 9.37

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 throughaqueous pores or carriage of such molecules across membranes with the bulk passage of waterin the GI tract can be expected. Furthermore uptake by passive diffusion is likely based on its moderate log Kow values. 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 substancecould be absorbed in the human body via the oral route. This is supported by the findingsin an OECD TG 422 feeding study that was performed with the read across source substance Cedarwood Virginia oil, which contains the same constituents with some variations in their concentration. The source substance induced systemic effects such as nephropathy in male rats. Furthermore, liver effects and reduced T4 levels were observed. These findings confirm that systemic absorption of the constituents of the UVCB via the gastrointestinal tract takes 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). No acute dermal toxicity was observed in rabbits exposed to 5000 mg/kg bw was observed in the acute dermal toxicity test performed with the read across substance Cedarwood Virginia oil.

 

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: 3 mg/cm2 (due to the high melting points of constituents);

Thickness of stagnant air: 10 cm;

Weight fraction: 1;

Observation time: up to total absorption or evaporation;

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 conc.(% w/w)Terpenes 1 (Cedrene)

Typical conc.(% w/w)Terpenes 2 (Thujopsene)

MW

Vapour pressure(Pa)

Water solubility (mg/L)

Log Kow

Density(g/mL)

Melting point

Max skin adh. (mg/cm2)

Weighted Dermal max absorption

Terpenes 1 (Cedrene)

Weighted Dermal max absorption

Terpenes 2 (Thujopsene)

Thujopsene

470-40-6

34.63%

58.00%

204.36

9.37

0.05999

6.12

1

48.5

10

0.0793%

0.1328%

Cedrene alpha

469-61-4

32.74%

15.00%

204.36

0.0184

0.04258

5.74

0.9

43.77

9

2.3049%

1.0560%

Cedrene beta

546-28-1

11.07%

5.00%

204.36

6.08

0.03202

5.82

0.9

41.79

9

0.0219%

0.0099%

Chamigrene beta

18431-82-8

1.19%

3.00%

204.36

3.05308

0.76453

7.02

0.9

48.82

9

0.0205%

0.0516%

Chamigrene alpha

19912-83-5

2.06%

3.00%

204.35

2.28

1.0168

6.94

0.9

50.66

9

0.0424%

0.0618%

Cuparene

16982-00-6

1.40%

3.00%

202.34

0.773

0.50078

6.19

0.9

60.05

9

0.0040%

0.0087%

Cedrol

 

77-53-2

0.93%

6.00%

222.37

0.0165

8.7229

4.33

1

75.52

10

0.1516%

0.9780%

Duprezianene alpha

79801-29-9

0.90%

0.50%

204.35

4.52

0.04258

5.74

0.9

84.85

9

0.0016%

0.0009%

gamma-Acoradiene

28400-12-6

0.83%

0.50%

204.35

2.32

1.1378

7.04

0.9

41.04

9

0.0220%

0.0133%

Himachalene beta

1461-03-6

0.76%

x

204.35

1.47

1.1378

6.35

0.9

54.06

9

0.0148%

x

Himachalene alpha

3853-83-6

0.68%

0.50%

204.35

0.0165

0.54268

6.3

0.9

43.42

9

0.0088%

0.0065%

beta-Acoradiene

28477-64-7

0.67%

0.50%

204.35

4.41

0.54268

6.99

0.9

29.52

9

0.0120%

0.0090%

Caryophyllene beta

87-44-5

1.09%

0.50%

204.36

4.16

0.54268

6.3

0.9

43.42

9

0.0099%

0.0045%

alpha-Funebrene

50894-66-1

0.13%

x

204.35

0.0184

0.04258

5.74

0.925

85.04

9.25

0.0039%

x

Total

 

89.1%

95.5%

 

 

 

 

 

 

 

 

 

 

The weighted permeability of the whole UVCB, calculated using the IH Skinperm tool was 3.03% for Terpenes 1 (Cedrene) and 2.44% for Terpenes 2 (Thujopsene). The worst case absorption number 3.03% 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. These physico-chemical propertieswould also facilitate absorption directly across the respiratory tract epithelium following aspiration.

 

Distribution

Distribution of Cedarwood Texas Terpenes – Cedrene (Type 1) and Thujopsene (Type 2) and its major constituents is expected based on their relatively low molecular weights. Also distribution throughout the body would be possible due to the low to moderate water solubility, while the higher Log Kow range also 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 at least distributed to the liver and kidney.

 

Metabolism

No information on metabolism can be derived from the physicochemical data that is available for Cedarwood Texas Terpenes – Cedrene (Type 1) and Thujopsene (Type 2). No information on metabolism of the UVCB is available from studies, but the main constituents of the UVCB substance; Thujopsene, Cedrol and Cedrene α/β are known to have an (inhibitory) effect on Cytochrome p450 enzyme activities[1]. Hepatic phase 1 metabolism mediated by P450 is therefore a likely mechanism. This is expected to be followed by attachment of the phase II polar groups in the liver before elimination. Hepatic involvement is supported by the liver effects that were observed in the OECD TG 422 read-across study.

Elimination

Based on the systemic renal effects observed in the OECD TG 422 read-across 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 around 300 do not tend to be excreted into the bile (Renwick, 1994)[1]. 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)[2].

Data from other studies

 

Cedarwood Texas Terpenes – Cedrene (Type 1) and Thujopsene (Type 2)

Skin irritation / corrosivity

Cedarwood Texas oil distilled - Terpenes (Thujopsene): not irritant

Cedarwood Texas oil distilled - Terpenes (Cedrene): irritant (read-across from Cedarwood Virginia oil)

Cedarwood Texas oil distilled - Terpenes (Cedrene): not corrosive (read-across from Cedarwood Virginia oil)

Acute Oral toxicity data

Cedarwood Texas oil distilled - Terpenes LD50> 5000 mg/kg bw (read-across from Cedarwood Virginia oil)

Acute Dermal toxicity data

Cedarwood Texas oil distilled - Terpenes LD50> 5000 mg/kg bw (read-across from Cedarwood Virginia oil)

Skin sensitisation data

Cedarwood Texas oil distilled - Terpenes (Thujopsene): not sensitising

Cedarwood Texas oil distilled - Terpenes (Cedrene): sensitising (read-across from Cedarwood Virginia oil)

Repeated dose toxicity

Nephropathy in male rats (hyaline droplet accumulation), hepatocellular hypertrophy in female rats.(read across from Cedarwood Virginia oil)

Conclusion

Oral uptake expected based on information from available studies (acute and repeated dose oral toxicity) and favourable physico chemical parameters. Dermal absorption would be possible based on physicochemical parameters. Relatively wide distribution and excretion through urine expected based on low/moderate 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 3.03% for the dermal route.

[1]Hyeon-Uk Jeong, Soon-Sang Kwon, Tae Yeon Kong, Ju Hyun Kim & Hye Suk Lee (2014). Inhibitory Effects of Cedrol, β-Cedrene, and Thujopsene on Cytochrome P450 Enzyme Activities in Human Liver Microsomes. Journal of Toxicology and Environmental Health, Part A Vol. 77 , Iss. 22-24.

[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 (%):
3.03
Absorption rate - inhalation (%):
100

Additional information