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Administrative data

Description of key information

Acute oral toxicity: > 5000 mg/kg bw, based on read-across from Beta-pinene, which was tested in OECD TG 401.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Remarks:
Beta-pinene
Adequacy of study:
key study
Study period:
The study was conducted in 1975.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
The information is used for read across to Rosemarel
Reason / purpose:
read-across: supporting information
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ace Animals
- Weight at study initiation: 235-287 g
- Fasting period before study: 16-20 hours
- Housing: 5/cage in suspended wire mesh cages. Bedding was placed beneath the cages.
- Diet: fresh Purina Rat Chow (Diet #5012), ad libitum, except 16-20 hours prior to dosing
- Water: ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Beta-pinene was administered by gavage at one dose of 5000 mg/kg bw.
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
10 males/dose
Control animals:
no
Details on study design:
- Frequency of observations: Animals were observed 3-4 hours post dosing and once daily thereafter for 14 days for mortality, toxicity and pharmacological effects.
- Necropsy of survivors performed: yes
- Other examinations performed: mortality, toxicity and pharmacological effects.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
One rat died on day 7.
Clinical signs:
No symptoms observed.
Body weight:
No information provided.
Gross pathology:
No information provided.
Other findings:
No other findings were noted.
Interpretation of results:
other: Not classified
Remarks:
According to EU CLP 1272/2008 and its amendments.
Conclusions:
The acute oral LD50 for the substance in rats was determined to be greater than 5000 mg/kg bw.
Executive summary:

Acute oral toxicity was performed with Beta-pinene similar to the guideline OECD TG 401. Ten male rats were used and they were administered the substance at the dose of 5000 mg/kg bw. One rat of ten died during the study on day 7. No symptoms in rats were observed. The acute oral LD50 for the substance in rats was determined to be greater than 5000 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Information is based on read across
Justification for type of information:
The full read-across document can be found in the Endpoint Summary in text and in the attached file.
Reason / purpose:
read-across source
GLP compliance:
no
Test type:
other: read across information
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Interpretation of results:
other: Criteria for classification are not met
Remarks:
according to EU CLP (EC 1272/2008 and its amendments)
Conclusions:
Rosemarel has an LD50 > 5000 mg/kg bw based on read across from Beta-pinene which was tested in a study similar to OECD TG 401.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

The acute oral toxicity of Rosemarel was assessed using read across from Beta-pinene (CAS# 127-91-3). First the study with the analogue is described and thereafter the read across justification is presented.

Acute oral toxicity study with Beta-pinene:

Acute oral toxicity was performed with Beta-pinene similar to the guideline OECD TG 401, pre-GLP. Ten male rats were used and they were administered the substance at the dose of 5000 mg/kg bw. One rat of ten died during the study on day 7. No symptoms in rats were observed. The acute oral LD50 for the substance in rats was determined to be greater than 5000 mg/kg bw.

The acute oral toxicity of Rosemarel using read across from Beta-pinene (CAS#127-91-3)

 

Introduction and hypothesis for the analogue approach

Rosemarel is a multi-constituent. The major part is the constituent Beta-pinene (51%) and this constituent has a hexyl ring bridged with one carbon, to which two methyl groups are attached. At the alpha position there is a double bonded methyl group attached to the hexyl ring, which is the functional group. The minor constituent (36%) has the same backbone. The functional group is an epoxide in the place where there is the double bonded methyl group in the other component. For Rosemarel data on acute oral toxicity are lacking.

In accordance with Article 13 of REACH, lacking information should be generated whenever possible by means other than vertebrate animal tests, i. e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For assessing the acute oral toxicity of Rosemarel the analogue approach is selected because for one closely related analogue acute oral toxicity information is available which can be used for read across.

Hypothesis: Rosemarel has similar acute oral toxicity compared to the Beta-pinene, resulting in a similar LD50. Although Beta-pinene as such presents a different reactivity than the epoxide constituent of Rosemarel, once systemically available, Beta-pinene will be partly oxidized to epoxide, so the target and source substances will be very similar and are predicted to have similar systemic toxicity.

Available information: The source chemical Beta-pinene has been tested in a an acute oral toxicity test with 10 rats (Moreno, 1975; similar to OECD TG 401, non-GLP) with one dose of 5000 mg/kg bw and the test result receives a reliability of 2.

 

Target chemical and source chemical(s)

The target is Rosemarel, and the source is Beta-pinene. Chemical structures of the target chemical and the source chemical are shown in the data matrix below. Also physico-chemical properties thought to be relevant for acute oral toxicity are listed in there. 

 

Purity / Impurities

Rosemarel consists of Beta-pinene (51 %) and its oxidised form- the epoxide (36 %). The impurities are all below < 10%.

 

Analogue approach justification

According to Annex XI 1.5, read across can be used to replace testing when the similarity can be based on a common backbone and a common functional group. When using read across, the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation.

Analogue selection:

Beta-pinene was selected as an analogue because it is Rosemarel’s major constituent, and when it is oxidised, Beta-pinene becomes Rosemarel’s minor constituent.

Structural similarities and differences:

Rosemarel contains 51% Beta-pinene and thus the overlap between the analogues is already 51%. The epoxide constituent has the same backbone as Beta-pinene but the double bond is oxidized into the epoxide component of Rosemarel.

Toxico-kinetic:

Absorption: Rosemarel’s constituents (Beta-pinene and Rosemarel’s epoxide) have similar absorption potential based on the fact of being liquids, on their low molecular weight (ca. 150) and on their physico-chemical properties that favour oral absorption (e.g. log Kow around 3.2 - 4.4).

Metabolisation: Beta-pinene will oxidize into the epoxide during the metabolisation and thereafter both constituents of Rosemarel will follow a similar pathway.

 

 

 

Fig. The sequence of Phase 1 metabolic steps for Rosemarel’s Beta-pinene (1ststructure), Rosemarel’s epoxide (2ndstructure) and the hydrolysed product (3rdstructure), which are possibly conjugated during Phase 2 metabolic pathways.

Uncertainty of the prediction:

There is no remaining uncertainty. First of all, Rosemarel contains 51% of Beta-pinene and secondly, Beta-pinene will oxidize to the epoxide during metabolization. This means that also for the epoxide constituent the LD50 > 5000 mg/kg bw can be anticipated.

 

Conclusions per endpoint for C&L and dose descriptor

When using read across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation.For Beta-pinene a well conducted acute oral toxicity test is available (Reliability2) with an LD50 > 5000 mg/kg bw. Based on these data for Beta-pinene, also for Rosemarel an LD50 > 5000 mg/kg bw can be derived.

 

Final conclusion on hazard and C&L: Rosemarel has an LD50 > 5000 mg/kg bw.

 

Data matrix: Information to support the read across for Rosemarel from Beta-pinene to assess the acute oral toxicity of Rosemarel.

Name of substance

Rosemarel and its two constituents: Beta-pinene and its oxidation product

Beta-pinene

Chemical structure

Empirical

C10H16 and C10H16O

C10H16

Cas No

127-91-3 and 6931-54-0, respectively

127-91-3

REACH registration

To be registered for 2018

Registered (2010)

EINECS

-

242-060-2

Mol weight

136.24 and 152.24

136.24

Phys-chem

 

 

Appearance

Colourless to slight yellow liquid (IFF, 2016)

Liquid

Melting point(oC)

<-20 (IFF, 2016)

-20 (ECHA site)

Boiling point (oC)

173.85 (C)

172.2 (IFF, 2016)

150.80 (C)

166-179 (ECHA site)

Vapour pressure (Pa at 25oC)

345.9 (IFF, 2016)

851 (ECHA site)

Water solubility (mg/l)

7.1 and 338 (C)

45.7 (IFF, 2016)

7.1 (C)

6.95 (ECHA site)

Log Kow

4.35 and 2.95 (C)

3.2-3.4 (IFF, 2016)

4.35 (C)

4.4 (ECHA site)

Human health

 

 

Acute oral toxicity (mg/kg bw)

Read across from Beta-pinene

LD50 > 5000

C: calculated value, the physico-chemical data were generated with EPISuite (version 4.1).

Justification for classification or non-classification

The substance does not need to be classified for acute toxicity by the oral route, based on the EU CLP regulation (1272/2008) and its amendments.