Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acute toxicity: oral: LD50 > 2000 mg/kg bw (OECD 401 in rats and mice; WoE, rel.2 and read-across, OECD 420, GLP, WoE, rel. 1);
Acute toxicity: dermal: LD50 > 2000 mg/kg bw (similar to OECD 402, K, rel. 2);
Acute toxicity: inhalation: waiver.

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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Further information is included as attachment to IUCLID section 13]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across approach is based on the hypothesis that the source and target substances have similar physico-chemical, toxicological, ecotoxicological and environmental fate properties because of their structural similarity.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target and the source substances (Table 1) are Cycloalkane ethers. The source substance is the racemic form, while the target substance is the (-)-isomer.

3. ANALOGUE APPROACH JUSTIFICATION
The source substance is expected to have similar toxicological profile than the target substance considering the respective physico-chemical and toxicological properties.
The study design (OECD 420, GLP) is adequate and reliable for the purpose of the prediction based on read-across. The test material used represents the source substance as described in the hypothesis in terms of purity and impurities. The results of the studies are adequate for the purpose of classification and labelling.
Therefore, based on the considerations above, it can be concluded that the results of the acute toxicity study conducted in the rat with the source substance are likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirement of Annex VII, 8.5.1.

4. DATA MATRIX
See IUCLID section 13
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
Preliminary study:
In the absence of mortality at a dose level of 2000 mg/kg bw, an additional group of animals was treated at the same dose level.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
other: Ataxia and/or hunched posture were noted in all animals during the day of dosing. All animals appeared normal one day after dosing.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of the study , the Oral LD50 Females > 2000 mg kg bw. The target substance has the same molecular weight than the source substance so no correction is needed for this LD50 which is therefore higher than 2000 mg/kg bw for the target substance.
Executive summary:

In an acute oral toxicity study performed according to the OECD test guideline No. 420 and in compliance with GLP, groups of fasted, eight to twelve weeks of age Wistar (RccHanTM:WIST) female rats were given a single oral dose of ST 10 C 08 as a suspension in Arachis oil BP.


Following a sighting test using one animal at a dose level of 2000 mg/kg bw, an additional four fasted female animals were given a single oral dose of test item, at the same dose level. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.


 


Oral LD50 Females > 2000 mg/kg bw


 


There were no deaths during the study.


Ataxia and/or hunched posture were noted in all animals during the day of dosing.


All animals showed expected gains in bodyweight.


No abnormalities were noted at necropsy.


 


Under the test conditions, ST 10 C 08 is not classified as toxic if swallowed according to the annex I of the Regulation (EC) No. 1272/2008 (CLP).


 


This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.


The target substance has the same molecular weight than the source substance so no correction is needed for this LD50 which is therefore higher than 2000 mg/kg bw for the target substance. The supporting substance is considered adequate for read-across purpose as data relates to the racemic form of the registered substance (see IUCLID section 13 for additional justification).

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Between 16 October 2012 and 15 November 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study performed according to OECD test guideline No. 420 and in compliance with GLP.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
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. QA statement)
Remarks:
UK GLP (Inspected on 10 July 2012 / Signed on 30 November 2012)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS (RccHanTM:WISTAR)
- Source: Harlan Laboratories UK Ltd, Oxon UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 153-168 g
- Fasting period before study: overnight. Food will be returned approximately 3 to 4 hours after dosing.
- Housing: grouped in group of up to four in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): Rodent 2014C Teklad Global Certified Diet ad libitum. Not contaminated.
- Water (e.g. ad libitum): Tap water ad libitum. Not contaminated.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION (if unusual): the test item was formulated within two hours of being applied in the test system. It is assumed that the formulation was stable for this duration.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Sighting test: 1 female
Main test: 4 additional females
Control animals:
no
Details on study design:
SIGHTING TEST
- a single animal, 2000 mg/kg bw

MAIN TEST
- 5 animals per dose level (made up of one animal from the sighting test dosed at the selected dose level together with an additional 4 animals)
- Duration of observation period following administration: 14 days
- Frequency of mortality / morbidity inspection: twice daily, early and late, during normal working dates, once daily at weekends and public holidays.
- Frequency of clinical observations: 30 min, 1, 2 and 4 hours after dosing, then at least once daily.
- Weighing: recorded on Day 0 (prior to dosing), Day 7 and 14, or at death.
- Necropsy of survivors performed: yes, gross necropsy on all animals
Statistics:
None
Preliminary study:
In the absence of mortality at a dose level of 2000 mg/kg bw, an additional group of animals was treated at the same dose level.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
other: Ataxia and/or hunched posture were noted in all animals during the day of dosing. All animals appeared normal one day after dosing.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Oral LD50 Females > 2000 mg kg bw.
Executive summary:

In an acute oral toxicity study performed according to the OECD test guideline No. 420 and in compliance with GLP, groups of fasted, eight to twelve weeks of age Wistar (RccHanTM:WIST) female rats were given a single oral dose of ST 10 C 08 as a suspension in Arachis oil BP.

Following a sighting test using one animal at a dose level of 2000 mg/kg bw, an additional four fasted female animals were given a single oral dose of test item, at the same dose level. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Oral LD50 Females > 2000 mg/kg bw

There were no deaths during the study.

Ataxia and/or hunched posture were noted in all animals during the day of dosing.

All animals showed expected gains in bodyweight.

No abnormalities were noted at necropsy.

Under the test conditions, ST 10 C 08 is not classified as toxic if swallowed according to the annex I of the Regulation (EC) No. 1272/2008 (CLP).

This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

The supporting substance is considered adequate for read-across purpose as data relates to the racemic form of the registered substance (see Iuclid section 13 for additional justification).

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
From October 10 to October 31, 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Study performed according to OECD test guideline No. 401 but not following GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Fü-Albino outbred stock Ibm:RORO (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Biological Research Laboratories (BRL) CH-4414 Füllinsdorf, Switzerland.
- Age at study initiation: no data
- Weight at study initiation: M: 124.5-140 g ; F: 117-126 g
- Fasting period before study: overnight before treatment, animals were given food again 4 hours after application of the test compound.
- Housing: max 3 per cage
- Diet (e.g. ad libitum): KLIBA 25-343, complete rodent maintenance diet ad libitum.
- Water (e.g. ad libitum): Tap water ad libitum.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±10
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: 30, 60, 120 and 240 minutes after application and then daily
- Weighing: immediately before treatment and on day 7 and 14.
- Necropsy of survivors performed: yes (CO2 asphyxia)
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality
Clinical signs:
other: None
Gross pathology:
No pathological changes
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Oral LD50Combined > 2000 mg/kg bw
Executive summary:

In an acute oral toxicity study performed according to OECD test Guideline No 401, groups of Fü-Albino outbred stock Ibm:RORO (SPF) rats (5/sex) were administered a single oral dose of 2000 mg/kg bw by gavage. The animals were observed for mortality, clinical signs, behaviour and appearance and then necropsied for macroscopic observations. 5 control rats per sex received a standard suspension vehicle.

None of the animals died during the study. No clinical signs were noted and weight gain was within normal range. No signs of gross pathological change were found by necropsy.

Oral LD50Combined > 2000 mg/kg bw

 

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

This study is considered as acceptable within a weight-of-evidence approach to satisfy the requirement for acute oral toxicity endpoint

 

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Basic data given: comparable to OECD guideline No 401.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
mouse
Strain:
CF-1
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: adult
- Weight at study initiation: ca. 25g (25.12)
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): Altromin Haltungsdiät Nr. 1324
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: no data
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE: CMC/MED/Type 70 (2%)

MAXIMUM DOSE VOLUME APPLIED: 20 cm3/kg (99.5 g/L)
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
10 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
Statistics:
Not applicable
Preliminary study:
Not applicable
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
None
Clinical signs:
other: None
Gross pathology:
No findings
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Mice Oral LD50(males) > 2000 mg/kg bw
Executive summary:

In an acute oral toxicity study performed similarly to OECD test Guideline No 401, CF-1 mice (10 males) were administered a single oral dose of Ambroxan diluted in CMC, at 2000 mg/kg bw by gavage. The animals were observed for 14 days.

None of the animals died during the study. No clinical signs were noted and weight gain was within normal range. No signs of gross pathological change were found by necropsy.

Mice Oral LD50(males) > 2000 mg/kg bw

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

This study is considered as acceptable within a weight-of-evidence approach to satisfy the requirement for acute oral toxicity endpoint

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The two studies performed on the registered substance in rats and mice were non-GLP, but followed or were similar to OECD Test guideline No 401. The study performed on the source substance was performed according to OECD test guideline No. 420 and in compliance with GLP.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
No effects were observed in rats following a 2-hours whole-body exposure to 1 % test substance. Although not fully reliable, this study demonstrated the lack of toxicity of the substance following inhalation exposure. In addition, the low vapour pressure of the substance (0.066 Pa at 20°C) combined with the large particle size (97.2% of particles > 100 µm) indicated an absence of volatility and inhalability; therefore low exposure potential by inhalation is anticipated from dust. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance. Moreover, in accordance with column 2 of REACH Annex VIII (§8.5), an additional acute toxicity by inhalation does not need to be conducted since the acute toxicity study is already provided for the oral and dermal routes.
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 1979-07-10 to 1979-07-24
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Although conducted under worst-case conditions (abraded skin, occlusive dressing), no mortality was observed during this study. A repeat study is unlikely to show worse effects; therefore this study was considered sufficiently robust to cover this endpoint.
Principles of method if other than guideline:
The abraded skin of albino rabbits (3/sex) was occlusively exposed to undiluted test material for 24 hours at dose of 2000 mg/kg bw. The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations.
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.0 - 3.0 kg bw
No other data
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE: abraded skin
- Area of exposure: back
- % coverage: no data
- Type of wrap if used: the treated areas were covered with large gauze patches and an impervious material was wrapped snugly around the trunk of each animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data, any excess material was removed
- Time after start of exposure: 24h
Duration of exposure:
24h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3 animals/sex
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: yes
Statistics:
none
Preliminary study:
not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
None
Clinical signs:
other: There were no unusual behavioural signs noted.
Gross pathology:
No effect
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Dermal LD50Combined > 2000 mg/kg bw
Executive summary:

In a limit acute dermal toxicity study performed similarly to the OECD guideline No. 402, the abraded skin of albino rabbits (3/sex) was occlusively exposed to undiluted test material for 24 hours at dose of 2000 mg/kg bw. The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations.

 

No mortality occurred during the study. There were no adverse effects.

 

Dermal LD50Combined > 2000 mg/kg bw

 

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

This study is considered as acceptable and satisfies the requirement for acute dermal toxicity endpoint

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
In the key study, conducted under worst-case conditions (abraded skin, occlusive dressing), no mortality was observed. An additional dermal study is unlikely to show worse effects, therefore this study was considered sufficiently robust to cover this endpoint.

Additional information

Acute toxicity: oral


A weight-of-evidence approach was used to conclude on the acute oral toxicity potential. The two studies performed on the registered substance in rats (Hoffmann, 1991) and in mice (Henkel, 1981) were non-GLP, but followed or were similar to OECD Test guideline No 401. The study performed on the source substance (Harlan, 2013) was performed according to OECD test guideline No. 420 and in compliance with GLP.


The two studies gave an oral LD50 (rats and mice) > 2000 mg/kg bw.


The study on the source substance gave an oral LD50 (rats) > 2000 mg/kg bw. The target substance has the same molecular weight than the source substance so no correction is needed for this LD50 which is therefore higher than 2000 mg/kg bw for the target substance.


There were no deaths during the studies. No clinical signs were noted and all animals showed expected gains in bodyweight. No abnormalities were noted at necropsy.


 


Acute toxicity: dermal


A key study was identified (Biosearch, 1979, rel.2). In this limit acute dermal toxicity study, which was performed similarly to the OECD guideline No. 402, the abraded skin of albino rabbits (3/sex) was occlusively exposed to undiluted test material for 24 hours at dose of 2000 mg/kg bw. The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations. No mortality occurred during the study. There were no adverse effects.


Dermal LD50Combined > 2000 mg/kg bw


 


Acute toxicity: inhalation
No effects were observed in rats following a 2-hours whole-body exposure to 1 % test substance. Although not fully reliable, this study demonstrated the lack of toxicity of the substance following inhalation exposure. In addition, the low vapour pressure of the substance (0.066 Pa at 20°C) combined with the large particle size (97.2% of particles > 100 µm) indicated an absence of volatility and inhalability; therefore low exposure potential by inhalation is anticipated from dust. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance.
Moreover, in accordance with column 2 of REACH Annex VIII (§8.5), an additional acute toxicity by inhalation does not need to be conducted since the acute toxicity study is already provided for the oral and dermal routes.

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 on the registered substance and on analogue substance, the substance is not classified according to the Regulation (EC) No. 1272/2008 as the LD50 is greater than 2000 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 as the LD50 is greater than 2000 mg/kg bw.


Acute toxicity (Inhalation):


No data was available.


Specific target organ toxicity: single exposure (Oral):


The classification criteria according to the Annex I of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral) for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw≥C > 300 mg/kg bw). No classification is required.


Specific target organ toxicity: single exposure (Dermal):


The classification criteria according to the Annex I of the Regulation (EC) No 1272/2008 as specific target organ toxicant (STOT) – single exposure, dermal are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (dermal) for a Category 1 classification (C≤ 1000 mg/kg bw) and at the guidance value (dermal) for a Category 2 classification (2000 mg/kg bw≥C > 1000 mg/kg bw). No classification is required.


Specific target organ toxicity: single exposure (Inhalation):


No data was available.