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Administrative data

Description of key information

Acute oral (based on read across from Vetival tested in an OECDTG401: LD50 > 2000 mg/kg bw

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
Adequacy of study:
key study
Study period:
6 August 1991 - 22 August 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crl.: (WI) Br - Wistar, white
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Firma Charles River Wiga, Sandhofer Weg 7, 8741 Sulzfeld
- Weight at study initiation: male: 172 - 190 g, female: 150 - 164 g
- Fasting period before study: The animals were fasted from 16 h before until 3 - 4 h after administration of the test article.
- Housing: collective housing up to a maximum of 5 animals per cage (Macrolon type III)
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS (set to maintain)
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2.2 mL/kg bw


CLASS METHOD: A preliminary range finding test with a dose of 2000 mg/kg body weight was conducted using two female rats.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 animals per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Body weights were recorded immediately before treatment (day 0) and an days 7 and 14 p.a. (termination).
- Necropsy of survivors performed: The animals were sacrificed by CO2 asphyxiation after 14 days and gross pathological examinations were subsequently performed.
- Other examinations performed: clinical signs
Preliminary study:
There were no deaths in the preliminary study.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals died during the course of the main study.
Clinical signs:
No abnormal clinical signs were observed.
Body weight:
Weight gains were normal in all animals.
Gross pathology:
Gross pathological examinations at 14 days p.a. (terminal necropsy) revealed no test article dependent findings.
Interpretation of results:
other: Not acute harmful.
Remarks:
According to Regulation (EC) No. 1272/2008 and its amendments
Conclusions:
The acute oral toxicity test with the substance showed an LD50 of >2000 mg/kg bw.
Executive summary:

In this study performed according to OECD TG 401 guideline and GLP principles, 10 rats (5 males and 5 females) were administered with the substance at a dose level of 2000 mg/kg bw. None of the animals died. No abnormal clinical signs were observed. Gross pathological examinations at 14 days p.a. (terminal necropsy) revealed no test article dependent findings. Based on the results in this study, the acute oral LD50 for the substance in male and female rats was determined to be >2000 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read across information
Justification for type of information:
The read across documentation is presented in the Acute toxicity Endpoint summary and the accompanying files are also attached there.
Reason / purpose for cross-reference:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Interpretation of results:
other: Not acute harmful.
Remarks:
According to Regulation (EC) No. 1272/2008.
Conclusions:
The acute oral LD50 of the target substance is considered to be >2000 mg/kg bw, based on the information of the source substance.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Acute oral is being read-across from Vetival to Herbac. The executive summary of the source is presented below followed by the read-across rationale.

Acute oral toxicity of Vetival:

In this study performed according to OECD TG 401 guideline and GLP principles, 10 rats (5 males and 5 females) were administered with the substance at a dose level of 2000 mg/kg bw. None of the animals died. No abnormal clinical signs were observed. Gross pathological examinations at 14 days p.a. (terminal necropsy) revealed no test article dependent findings. Based on the results in this study, the acute oral LD50 for the substance in male and female rats was determined to be >2000 mg/kg bw.

The acute oral toxicity of Herbac (CAS 25304-14-7) using read across from Vetival (CAS 4927-39-3)

Introduction and hypothesis for the analogue approach

Herbac is a cyclohexane substituted with an acetyl group (containing a ketone) at C-1 and two methyl groups at C-3. For this substance no acute oral toxicity data are available.

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 Herbac the analogue approach is selected. This is because for one closely related analogue acute oral toxicity information is available, which can be used for read across.

Hypothesis: Herbac has similar acute oral toxicity compared to Vetival resulting in a similar LD50 because the substances are very similar in structure and therefore their toxico-kinetic and toxico-dynamic behaviour.

Available information: The source chemical Vetival has been tested in a well conducted acute oral toxicity test (OECD TG 401 under GLP) at a limit dose of 2000 mg/kg bw and the test result receives a reliability of 1.

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemical are shown in the data matrix, including physico-chemical properties and toxicological information, thought relevant for acute oral toxicity, of both substances.

Purity / Impurities

The purity and impurities of the target chemical do not indicate acute oral toxicity potential other than indicated by the parent substance. Herbac has one major constituent (generally above 80%) as presented in the data matrix. It has one minor constituent (CAS4436-59-3)which is very similar in structure and based on its structure has similar, limited, reactivity. Therefore this constituent is not considered further in the read across.

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: Aclear documentation is needed on the selection of potential source substances.In order to identify possible RA candidates, the RIFM database and OECD QSAR toolbox were used for search of analogues.In the QSAR tool using Tanimoto with 80% threshold for similarity no additional structures were found.From the identified analogues, Vetival is very similar in structure to Herbac and has reliable acute oral toxicity data.

Structural similarities and differences: The target and the source chemicals have a similar backbone and functional group, i.e. cyclohexane backbone with a ketone in the alkyl chain attached to the ring. Thepresence of the ketone as an acetyl substituent or 1,1-dimethylbutan-3-one substituent to the cyclohexane ringand the presence of the two methyl groups directly on the cyclohexane ring or on the butan-3-one substituent is not considered to significantly affect the LD50.

Toxico-kinetic:The source chemicals and the target chemicals indicate similar toxico-kinetic characteristics based on the similarity in chemical structure and physico-chemical properties. Herbac and Vetival have molecular weights and log Kows favourable for uptake via the oral route. The extra two C-atoms in Vetival result in somewhat higher log Kow and lower water solubility. With regard to metabolism, the ketone group in both substances can be reduced to the alcohol. All methyl groups may be oxidized to alcohols, aldehydes and/or acid after which conjugation is anticipated. The potential sites of oxidation or reduction are presented below in Fig. 1. In case the last C on the alkyl chain will be oxidized (not predicted in the OECD Toolbox) to an acid there will be a keto-acid, which may be more reactive. In view of both substances similarly vulnerable to such oxidation, this will not hinder the read across. OECD Toolbox presents a similar pattern of metabolites between both substances (data not shown).

Fig. 1 Sites of attack for oxidation and reduction based on Toxicological handbooks. The upper substance is Herbac, the lower one Vetival.

 

Toxico-dynamics: Both substances are predicted to be in Cramer class II and to be of intermediate toxicity, also all other profiles show a similar pattern as presented by the QSAR toolbox (Data not shown).

Uncertainty of the prediction:There are no remaining uncertainties.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the Data Matrix in Table 1.

Conclusions per endpoint for C&L: When using read across the result derived should be applicable for C&L and/or risk assessment, cover an exposure period duration comparable or longer than the corresponding method and be presented with adequate and reliable documentation. For Vetival a well conducted acute oral toxicity test is available (Reliability 1) with a LD50 exceeding 2000 mg/kg bw which does not lead to classification and labelling for this endpoint. Based on these data, for Herbac also a LD50 of >2000 mg/kg bw can be derived for the endpoint acute oral toxicity study and therefore classification is not needed.

Final conclusion on hazard and need for C&L:Herbac has an LD50 of >2000 mg/kg bw and does not need to be classified for acute oral toxicity.

Data matrix for the read across from Vetival to Herbac

Common names

Herbac

Vetival

Chemical structures

CAS no

25304-14-7

4927-39-3

EINECS

246-799-1

225-562-6

REACH registration

2018 deadline

Not found

Empirical formula

C10H18O

C12H22O

Physico-chemical data

 

 

Molecular weight

154.53

182.31

Physical state

liquid

liquid

Vapour pressure, Pa

78.1 Pa (EpiSuite)

50.2 (measured)

14.3 (Episuite)

Water solubility, mg/l

239.8 (EpiSuite)

639.7 (measured)

25.66 (EpiSuite)

Log Kow

2.91 (EpiSuite)

3.5 (measured)

3.89 (EpiSuite)

Human health endpoints

 

 

Acute oral tox in mg/kg bw

Read across

LD50 >2000 mg/kg bw

 

Justification for classification or non-classification

The substance does not have to be classified as acute orally toxic by the oral route in accordance with EU CLP (EC No. 1272/2008 and its amendments).