Registration Dossier

Administrative data

Description of key information

Acute toxicity: oral: LD50 > 2000 mg/kg bw (OECD 401 in rats and mice; WoE, rel.2);
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:
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:
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 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:
None
Body weight:
Normal weight gain
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:
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 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:
None
Body weight:
Normal weight gain (25.12 g at study initiation; 26.59 g at 48-hrs , 31.16 g at the end of week 1 and 34.04 g at study termination).
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.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
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 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:
There were no unusual behavioural signs noted.
Body weight:
No effect
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 two studies gave an oral LD50 (rats and mice) > 2000 mg/kg bw.

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, 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.