Registration Dossier

Administrative data

Description of key information

Acute toxicity: oral: LD50 > 2000 mg/kg bw (OECD 420, GLP, K, rel. 1).
Acute toxicity: dermal: LD50 > 2000 mg/kg bw, read-across substance (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
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
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.
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)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals 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 wooflakes.
- 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.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
Ataxia and/or hunched posture were noted in all animals during the day of dosing. All animals appeared normal one day after dosing.
Body weight:
All animals showed expected gains in bodyweight over the observation period.
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 Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies 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 key study is GLP compliant and of high quality (Klimisch score = 1)

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
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:
In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for sub stances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. In the present case, inhalation exposure will be lower than dermal exposure because the registered substance has a very low vapour pressure (0.054 Pa at 20°C), so the potential to generate vapor is low. Nonetheless, considering the use of the substance, exposure to mist can occur. However, based on the absence of acute toxicity by oral route, no mortality is anticipated during the exposure to mist. Hence, dermal exposure is the more likely route of exposure during the manufacture and the use of the substance leading to the low penetration of the substance based on its partition coefficient (Log Kow = 5.09°C).
Reason / purpose:
data waiving: supporting information
Clinical signs:
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:
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 Regulation EC No. 1272/2008 (CLP) and to the GHS.

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

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
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 target substance is the racemic form, while the source 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 (similar to OECD 402, 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 dermal 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 VIII, 8.5

4. DATA MATRIX
See Iuclid section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Remarks:
Read-across justification document
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 source substance 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 source and the target substances are not classified according to 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:
No study was located on the substance. Therefore a read-across approach on a supporting substance, one of its enantiomers, was used to fulfil this endpoint. No mortality was observed in the key study, although conducted under worst-case conditions (abraded skin, occlusive dressing). A repeat study is unlikely to show worse effects, therefore this study was considered sufficiently robust to cover this endpoint.

Additional information

Acute toxicity: oral

A key study was identified (Harlan, 2012). This acute oral toxicity study was performed according to the OECD test guideline No. 420 and in compliance with GLP. 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 ST 10 C 08, at the same dose level. 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.

Oral LD50 Females > 2000 mg/kg bw.

Acute toxicity: inhalation

In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for sub stances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. In the present case, inhalation exposure will be lower than dermal exposure because the registered substance has a very low vapour pressure (0.054 Pa at 20°C), so the potential to generate vapor is low. Nonetheless, considering the use of the substance, exposure to mist can occur. However, based on the absence of acute toxicity by oral route, no mortality is anticipated during the exposure to mist. Hence, dermal exposure is the more likely route of exposure during the manufacture and the use of the substance leading to the low penetration of the substance based on its partition coefficient (Log Kow = 5.09°C).

Acute toxicity: dermal

No study was located on the substance. Therefore a read-across approach using a supporting substance was used to fulfil this endpoint (Biosearch, 1979, Rel. 2). In this 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 PA 279 -4 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

The supporting substance is one of the enantiomers of the registered substance. The read-across is considered appropriate and scientifically justified based on the structural and physico-chemical similarity and the common toxicological profile of the two substances (see §Toxicokinetics for read-across justification).



Justification for classification or non-classification

Harmonised classification:

The substance has no harmonised classification for health hazards according to the Regulation (EC) No. 1272/2008 (CLP).

Self classification:

Acute toxicity via Oral route:

Based on the available data, the substance is:

- not classified according to the CLP as the LD50 is greater than 2000 mg/kg bw

- not classified according to the GHS as the LD50 is not expected to be in the range 2000 -5000 mg/kg bw.

Acute toxicity via Dermal route:

Based on the available data on a supporting substance, the test item is:

- not classified according to the CLP as the LD50 is greater than 2000 mg/kg bw

- not classified according to the GHS as the LD50 is not expected to be in the range 2000 -5000 mg/kg bw.

Acute toxicity via Inhalation:

No data was available.

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the CLP and to the GHS 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.

The criteria for Transient Organ effects (STOT-SE Category 3) according to the CLP and to the GHS are not met since narcotic effects were not observed in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Dermal):

The classification criteria according to the CLP and to the GHS 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.

The criteria for Transient Organ effects (STOT-SE Category 3) according to the CLP and to the GHS are not met since narcotic effects were not observed in the acute dermal toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

No data was available. However, the registered substance is not a skin or an eye irritant, therefore respiratory tract irritation is not expected.

 

Aspiration hazard:

The substance is not a hydrocarbon and no effects were observed on lungs in oral studies, therefore the criteria for aspiration toxicity according to the CLP and to the GHS are not met.