Registration Dossier

Administrative data

Description of key information

Based on a Read across strategy, two extract from the same plant were found to have an oral LD50 greater than 5000 mg/kg(OECD 423 & OECD 420 in rats; GLP, K, rel.1), and in an acute dermal toxicity, an extract from the same botanical specie has a DL50 greater that 5000 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:
weight of evidence
Study period:
08 - 23 August 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study performed according to OECD Guideline 423 with no deviation
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
dated 17 December, 2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
27 April 2017
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Elevage JANVIER LABS, France
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 169-206 g
- Fasting period before study: overnight. Redistributed 4 hours after the test item administration.
- Housing: Animals were housed by group of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid.
- Diet (e.g. ad libitum): Foodstuff (ENVIGO – 2016 Teklad Global 16% Protein Rodent Diet), ad libitum
- Water (e.g. ad libitum): Drinking water (tap-water from public distribution system), ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25°C
- Humidity: 30-70%
- Air changes: at least 10/hour
- Photoperiod: 12 hours dark / 12 hours light
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: ca. 2000 mg/10 mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: Olive oil was chosen as it produced the most suitable formulation at the requested concentration.

DOSAGE PREPARATION: In the first and second step of the study, 2.0090 g and 2.0098 g of the test item were weighed and Olive oil was added to two 10 mL volumetric flasks. Just before the administration, the preparations were stirred by vortex then magnetically during 5 minutes at approximately 50°C to obtain thick brown solutions.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 female rats
Control animals:
no
Remarks:
Historical data
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality were recorded at 30 min, 1h, 3h, 4h, 24h, 48h after administration of the test item and continued daily during 14 days.. Animals were weighed on day D0 (just before administering the test item) and then on D2, D7, and D14.
- Necropsy of survivors performed: Yes; animals were euthanized with sodium pentobarbital (Dolethal®) on D14 and macroscopic observations were noted.
Statistics:
No data
Preliminary study:
Not applicable
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: estimated from the flow chart from OECD Guideline 423 (Appendix 2d)
Mortality:
No mortality occurred during the study.
Clinical signs:
No clinical signs related to the administration of the test item were observed during the study.
Body weight:
The body weight evolution of the animals remained normal throughout the study.
Gross pathology:
The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw in rats. In accordance with OECD Guideline 423, the LD50 cut-off of the test substance may be considered to be higher than 5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and according to the Globally Harmonised System of classification and labelling of chemicals (GHS).
Executive summary:

In an acute oral toxicity study performed according to the OECD Guideline 423 and in compliance with GLP, a single dose of 2000 mg/kg bw of the test substance solubilized in olive oil and heated during 5 minutes at ca. 50°C was given by oral gavage to a group of 6 female Sprague Dawley rats. Animals were then observed for mortality, clinical signs and body weight changes for 14 days, and were all sacrificed for macroscopic examinations.

No mortality occurred during the study. No clinical signs related to the administration of the test item were observed during the study The body weight evolution of the animals remained normal throughout the study. The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.

Rat Oral LD50 >2000 mg/kg bw.

Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw in rats. In accordance with OECD Guideline 423, the LD50 cut-off of the test substance may be considered to be higher than 5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and according to the Globally Harmonised System of classification and labelling of chemicals (GHS).

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
March 03 to 26, 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study conducted in compliance with OECD Guideline 420 without any deviation.
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on March 12 to 14, 2014/ signed on May 12, 2014)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 159-176 g
- Fasting period before study: Animals were fasted for overnight period before dosing and for approximately 3-4 h after dosing.
- Housing: Animals were housed in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet: Food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 30-70 %
- Air changes: 15 changes / h
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: March 03 to 26, 2015
Route of administration:
oral: gavage
Vehicle:
DMSO
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: DMSO was used as vehicle because the test item did not dissolve/suspend in distilled water or arachis oil BP.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION: For the purpose of the study, the test item was freshly prepared, as required, as a suspension in dimethyl sulphoxide. The test item was formulated within 2 hours of being applied to the test system. It is assumed that the formulation was stable for this duration.
Doses:
- Sighting study: 300 and 2000 mg/kg bw
- Main study: 2000 mg/kg bw
No. of animals per sex per dose:
- Sighting study: 1 female/dose
- Main study: 5 females/dose (1 animal included from sighting study)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made 0.5, 1, 2, and 4 h after dosing and then daily for 14 days. Morbidity and mortality checks were made twice daily. Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
- Necropsy of survivors performed: Yes; at the end of the observation period, animals were killed by cervical dislocation and subjected to gross necropsy.
Statistics:
None
Preliminary study:
- No mortality or clinical signs were observed at 300 mg/kg bw.
- The animal showed expected gains in body weight over the observation period.
- No abnormalities were noted at necropsy.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed at 2000 mg/kg bw.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Rat Oral LD50 (females) > 2000 mg/kg bw
Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP).
Executive summary:

In an acute oral toxicity study performed according to OECD Guideline 420 and in compliance with GLP, groups (5 females/dose) of Wistar (RccHan™:WIST) rats were given a single oral (gavage) dose of test item at 2000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination. Sighting study was conducted at the dose levels of 300 and 2000 mg/kg bw (one female/dose) to determine the dose for main study.

 

In the sighting study, no mortality or clinical signs were observed at 300 mg/kg bw. The animal showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy. In the main study, no mortality or clinical signs were observed at 2000 mg/kg bw. All animals showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy.

 

Rat Oral LD50 (females) > 2000 mg/kg bw

 

Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP).

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Justification for type of information:
Resinoid of Cistus ladaniferus (Cistaceae) obtained from labdanum gum by organic solvents extraction and Gum of Cistus ladaniferus (Cistaceae) obtained from stems and leaves by extraction with alkaline solution are extracted from the same botanical plant: Cistus ladaniferus (Cistaceae)
Reason / purpose:
read-across source
Preliminary study:
Not applicable
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: estimated from the flow chart from OECD Guideline 423 (Appendix 2d)
Mortality:
No mortality occurred during the study.
Clinical signs:
No clinical signs related to the administration of the test item were observed during the study.
Body weight:
The body weight evolution of the animals remained normal throughout the study.
Gross pathology:
The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw in rats. In accordance with OECD Guideline 423, the LD50 cut-off of the test substance may be considered to be higher than 5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and according to the Globally Harmonised System of classification and labelling of chemicals (GHS). Therefore the registered substance is considered as non claissifed
Executive summary:

In an acute oral toxicity study performed according to the OECD Guideline 423 and in compliance with GLP, a single dose of 2000 mg/kg bw of the test substance solubilized in olive oil and heated during 5 minutes at ca. 50°C was given by oral gavage to a group of 6 female Sprague Dawley rats. Animals were then observed for mortality, clinical signs and body weight changes for 14 days, and were all sacrificed for macroscopic examinations.

No mortality occurred during the study. No clinical signs related to the administration of the test item were observed during the study The body weight evolution of the animals remained normal throughout the study. The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.

Rat Oral LD50 >2000 mg/kg bw.

Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw in rats. In accordance with OECD Guideline 423, the LD50 cut-off of the test substance may be considered to be higher than 5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and according to the Globally Harmonised System of classification and labelling of chemicals (GHS).

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Justification for type of information:
Concrete of Cistus ladaniferus (Cistaceae) obtained from stems and leaves by organic solvents extraction and Gum of Cistus ladaniferus (Cistaceae) obtained from stems and leaves by extraction with alkaline solution are extracted from the same botanical plant: Cistus ladaniferus (Cistaceae)
Reason / purpose:
read-across source
Limit test:
no
Preliminary study:
- No mortality or clinical signs were observed at 300 mg/kg bw.
- The animal showed expected gains in body weight over the observation period.
- No abnormalities were noted at necropsy.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed at 2000 mg/kg bw.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Rat Oral LD50 (females) > 2000 mg/kg bw
Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP). Therefore the registered substance is considered as not classified.
Executive summary:

In an acute oral toxicity study performed according to OECD Guideline 420 and in compliance with GLP, groups (5 females/dose) of Wistar (RccHan™:WIST) rats were given a single oral (gavage) dose of test item at 2000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination. Sighting study was conducted at the dose levels of 300 and 2000 mg/kg bw (one female/dose) to determine the dose for main study.

 

In the sighting study, no mortality or clinical signs were observed at 300 mg/kg bw. The animal showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy. In the main study, no mortality or clinical signs were observed at 2000 mg/kg bw. All animals showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy.

 

Rat Oral LD50 (females) > 2000 mg/kg bw

 

Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP). Therefore the registered substance is considered as not classified.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1971
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Reason / purpose:
read-across: supporting information
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not applicable
GLP compliance:
not specified
Test type:
fixed dose procedure
Specific details on test material used for the study:
clear, yellow liquid
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: from 2.5 to 3.0 Kg
- Housing: individually
- Diet : commercial diet
- Water ad libitum:
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 240 cm²
- % coverage: 10% of body surface
Duration of exposure:
24 hours
Doses:
5 ml/kg
No. of animals per sex per dose:
3 animals
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily (toxic effects, dermal reactions and mortality)
- Necropsy of survivors performed: yes
Key result
Dose descriptor:
LD50
Effect level:
> 5 mL/kg bw
Mortality:
No mortality was observed.
Clinical signs:
Erythema and edema were observed
Body weight:
No data
Gross pathology:
No data
Interpretation of results:
GHS criteria not met
Conclusions:
Under the experimental conditions of this study, the test substance is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to GHS.
Executive summary:

In an acute dermal toxicity study (limit test), three rabbits were given a single dermal application of labdanum at 5000 mL/kg bw. Animals were observed for mortality and clinical signs for 14 days.

No mortality was observed. Edema and Erythema were observed.

In this study, the dermal LD50 of the test item was higher than 5000 mL/kg bw in rats.

Under the experimental conditions of this study, the test item is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to GHS.

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1971
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Justification for type of information:
Labdanum oil and Labdanum gum are obtained from the same botanical source, the Cistus ladaniferus (Cistaceae).
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not applicable
GLP compliance:
not specified
Test type:
fixed dose procedure
Specific details on test material used for the study:
clear, yellow liquid
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: from 2.5 to 3.0 Kg
- Housing: individually
- Diet : commercial diet
- Water ad libitum:
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 240 cm²
- % coverage: 10% of body surface
Duration of exposure:
24 hours
Doses:
5 ml/kg
No. of animals per sex per dose:
3 animals
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily (toxic effects, dermal reactions and mortality)
- Necropsy of survivors performed: yes
Key result
Dose descriptor:
LD50
Effect level:
> 5 mL/kg bw
Mortality:
No mortality was observed.
Clinical signs:
Erythema and edema were observed
Body weight:
No data
Gross pathology:
No data
Interpretation of results:
GHS criteria not met
Conclusions:
Under the experimental conditions of this study, the test substance is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to GHS. Therefore, the registered substance is not considered toxic by dermal route.
Executive summary:

In an acute dermal toxicity study (limit test), three rabbits were given a single dermal application of labdanuml at 5000 mL/kg bw. Animals were observed for mortality and clinical signs for 14 days.

No mortality was observed. Edema and Erythema were observed.

In this study, the dermal LD50 of the test item was higher than 5000 mL/kg bw in rats.

Under the experimental conditions of this study, the test item is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to GHS. Therefore, the registered substance is not considered toxic by dermal route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Additional information

 Acute toxicity: oral

In an acute oral toxicity study performed according to the OECD Guideline 423 and in compliance with GLP, a single dose of 2000 mg/kg bw of the test substance solubilized in olive oil and heated during 5 minutes at ca. 50°C was given by oral gavage to a group of 6 female Sprague Dawley rats. Animals were then observed for mortality, clinical signs and body weight changes for 14 days, and were all sacrificed for macroscopic examinations.

 

No mortality occurred during the study. No clinical signs related to the administration of the test item were observed during the study The body weight evolution of the animals remained normal throughout the study. The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.

 

Rat Oral LD50 (Female) >2000 mg/kg bw.

 

Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw in rats. In accordance with OECD Guideline 423, the LD50 cut-off of the test substance may be considered to be higher than 5000 mg/kg bw by oral route in the rat.

 

Acute oral toxicity:

In an acute oral toxicity study performed according to OECD Guideline 420 and in compliance with GLP, groups (5 females/dose) of Wistar (RccHan™:WIST) rats were given a single oral (gavage) dose of test item at 2000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination. Sighting study was conducted at the dose levels of 300 and 2000 mg/kg bw (one female/dose) to determine the dose for main study.

 

In the sighting study, no mortality or clinical signs were observed at 300 mg/kg bw. The animal showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy. In the main study, no mortality or clinical signs were observed at 2000 mg/kg bw. All animals showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy.

 

Rat Oral LD50 (females) > 2000 mg/kg bw

 

Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and GHS..

Acute dermal toxicity:

In an acute dermal toxicity study (limit test), three rabbits were given a single dermal application of labdanuml at 5000 mL/kg bw. Animals were observed for mortality and clinical signs for 14 days.

No mortality was observed. Edema and Erythema were observed.

In this study, the dermal LD50 of the test item was higher than 5000 mL/kg bw in rats.

Under the experimental conditions of this study, the test item is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to GHS.Therefore, the registered substance is not considered toxic by dermal route.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Acute toxicity via Oral route:

Based on the available data the substance is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and to the Globally Harmonised System of classification and labelling of chemicals (GHS) as the oral LD50 is higher than 5000 mg/kg bw.

Acute toxicity via Dermal route:

Based on the available data the substance is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and to the Globally Harmonised System of classification and labelling of chemicals (GHS) as the oral LD50 is higher than 5000 mg/kg bw.

Acute toxicity (Inhalation):

No data was available.