Registration Dossier

Administrative data

Description of key information

Oral LD50 (females) > 2000 mg/kg bw (OECD 420, K, Rel.1, fixed dose method in rats)

Dermal LD50 (combined) > 2000 mg/kg bw (OECD 402, K, Rel.1, limit test in rats)

Inhalation LC50 (combined) > 5.31 mg/L (= 5310 mg/m3) (OECD 436, K, Rel.1, limit test/nose only in rats)

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:
02 October to 01 November 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted in compliance with OECD Guideline 420 without any deviation.
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
2001
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 July 10, 2012/ signed on November 30, 2012)
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.
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 151-165 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: 02 October to 01 November 2012
Route of administration:
oral: gavage
Vehicle:
other: unchanged (2000 mg/kg bw), Arachis oil BP (300 mg/kg bw)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 mg/mL
- 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 for 300 mg/kg bw
- 2.02 mL/kg bw for 2000 mg/kg bw (Specific gravity of test item - 0.992)

DOSAGE PREPARATION:
- For the purpose of the 2000 mg/kg dose level, the test item was used as supplied. For the purpose of the 300 mg/kg dose level, the test item was freshly prepared, as required, as a solution in arachis oil BP.
- The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.

JUSTIFICATION FOR DOSE SELECTION:
- Rationale for the selection of the starting dose: In the absence of data regarding the toxicity of the test item, 300 mg/kg bw was chosen as the starting dose.
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 the animals were killed by cervical dislocation and subjected to gross necropsy.
Statistics:
None
Preliminary study:
- No mortality or signs of systemic toxicity were noted at 300 and 2000 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.
Remarks on result:
other: no mortality was observed at 2000 mg/kg bw
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 bodyweight over the observation period.
Gross pathology:
Dark liver was noted at necropsy of one animal. No abnormalities were noted at necropsy of the remaining animals.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Rat Oral LD50 (females) > 2000 mg/kg bw. Under the experimental conditions of this study, the test item is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to GHS.
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 sighting study, no mortality or clinical signs were observed at 300 and 2000 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 was observed at 2000 mg/kg bw. No signs of systemic toxicity were noted during the observation period. All animals showed expected gains in bodyweight over the observation period. Dark liver was noted at necropsy of one animal at 2000 mg/kg bw. No abnormalities were noted at necropsy of the remaining animals.

 

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

 

Under the experimental conditions of this study, the test item is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to 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
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
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 September to 04 October 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted in compliance with OECD Guideline No. 436 without any deviation.
Qualifier:
according to
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
2009
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on July 10, 2012 / signed on September 07, 2012)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd, Oxon, UK.
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: Approximately 8-12 weeks
- Weight at study initiation: 200-350 g
- Housing: Animals were housed in groups of three by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes
- Diet: Food (Harlan 2014C Rodent Diet, 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: Fifteen changes per hour
- Photoperiod: 12 h dark / 12 h light

N-LIFE DATES: 13 September to 04 October 2012
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
1.93 µm
Geometric standard deviation (GSD):
2.65
Remark on MMAD/GSD:
Inhalable fraction (% < 4 µm) = 77.4
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Test item was aerosolised using a glass concentric jet nebuliser (Radleys, Saffron Walden, Essex, UK) located at the top of the exposure chamber. The nebuliser was connected to a glass syringe attached to an infusion pump, which provided a continuous supply of test item under pressure, and to a metered compressed air supply.
- Exposure chamber volume: Cylindrical exposure chamber had a volume of approximately 30 litres (dimensions: 28 cm diameter x 50 cm high).
- On the day of exposure each rat was acclimatised (for approximately 2 hours) to a tapered polycarbonate restraining tube.
- Method of holding animals in test chamber: During the exposure, each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and sealed by means of a rubber ‘O’ ring. Only the nose of each animal was exposed to the test atmosphere.
- Source and rate of air: Compressed air was supplied by means of an oil free compressor and passed through a water trap and respiratory quality filters before it was introduced to the nebuliser. Chamber flow rate was maintained at 60 L/min providing 120 air changes per hour.
- Method of particle size determination: The particle size of the generated atmosphere inside the exposure chamber was determined three times during the exposure period using a Marple Personal Cascade Impactor (Westech IS Ltd, Beds., UK).
- Treatment of exhaust air: The extract from the exposure chamber passed through a ‘scrubber’ trap and was connected with a high efficiency filter to a metered exhaust system. The chamber was maintained under negative pressure.
- Temperature and humidity in air chamber: Temperature and relative humidity inside the exposure chamber were measured by an electronic thermometer/humidity meter (Hanna Instruments Ltd, Beds., UK) located in a vacant port in the animals’ breathing zone of the chamber and recorded every thirty minutes throughout the four-hour exposure period.
- Exposure Chamber Oxygen Concentration: Oxygen levels within the exposure chamber were measured by an electronic oxygen analyser (Servomex (UK) Ltd, Crowborough, East Sussex) located in a port in the animals breathing zone during the four-hour exposure period. The test atmosphere was generated to contain at least 19% oxygen.
- Exposure Chamber Atmosphere Concentration:
Prior to the inhalation phase of the study, the non-volatile component of the test item was determined by adding a small, known amount of test item to glass fibre filters and recording their weights. The filters were then dried in a desiccator between 19 and 21°C for approximately 24 hours and then weighed again. The difference in the two weights was taken as the volatile content of the test item and the non-volatile component was calculated as a percentage. The mean non-volatile component of the batch used during the formal exposure was found to be 96.1 % (n=10).
The test atmosphere was sampled at regular intervals during the exposure period. A weighed glass fibre filter was placed in a filter holder and temporarily sealed in a vacant port of the exposure chamber in the animals’ breathing zone. A known quantity of the exposure chamber atmosphere was drawn through the filter using a vacuum pump.
After sampling, the filter was dried, under similar conditions as those previously described, and weighed again 24 hours later. The difference in the pre and post sampling weights, divided by the volume of atmosphere sampled, was the chamber concentration in terms of non-volatile component.
Based on the results of the preliminary work, these figures were adjusted to obtain a true figure for the test item concentration in the chamber.
The nominal chamber concentration was calculated by dividing the mass of test item disseminated into the chamber by the total volume of air that flowed through the chamber during the exposure.
The nominal concentration was 353 % of the actual mean achieved atmosphere concentration and shows that keeping the aerosol airborne was extremely difficult, even when generating an aerosol from a formulation of the test item.
- Pretreatment: Prior to the start of the study, test item atmospheres were generated within the exposure chamber. During this characterisation period test item input rates were varied to achieve the required atmospheric concentrations.
- Following an appropriate equilibration period a single group of six rats (three males and three females) was exposed to an atmosphere of the test item for a period of four hours. A target concentration of 5.0 mg/L was used for the exposure. As the mean achieved concentration was 106 % of target and no deaths occurred, no further levels were required.

TEST ATMOSPHERE
-Homogeneity of the test atmosphere within the chamber was not specifically determined during this study. Chambers of the same design (ADG Developments Ltd, Hitchin, Herts, UK) have been fully validated and shown to produce evenly distributed atmospheres in the animals’ breathing zone with a wide variety of test items (Green J D et al, 1984).
- Samples taken from breathing zone: Yes

TEST ATMOSPHERE
- Particle size distribution: See table 7.2.2/2
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.93 µm / 2.65
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
4 h
Concentrations:
Target concentration: 5 mg/L
Mean achieved atmosphere concentration: 5.31 ± 0.22 mg/L
Nominal concentration: 18.8 mg/L
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: All animals were observed for clinical signs at hourly intervals during exposure, immediately on removal from the restraining tubes at the end of exposure, one hour after termination of exposure and subsequently once daily for fourteen days. Any evidence of overt toxicity was recorded at each observation.
- Frequency of weighing: Individual bodyweights were recorded on arrival, prior to treatment on the day of exposure and on Days 1, 3, 7 and 14.
- Necropsy of survivors performed: Yes, At the end of the fourteen day observation period all animals were killed by intravenous overdose of sodium pentobarbitone. All animals, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded. The respiratory tract was subjected to a detailed macroscopic examination for signs of irritancy or local toxicity.
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.31 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: no mortality was observed
Mortality:
No mortality was observed.
Clinical signs:
- Signs of hunched posture, pilo-erection and red/brown staining around the eyes and snout are commonly seen in animals for short periods on removal from the chamber following 4-hour inhalation studies. Wet fur is commonly recorded both during and for a short period after exposure. These observations are considered to be associated with the restraint procedure and, in isolation, are not indicative of toxicity.
- In addition to the observations considered to be due to the restraint procedure, increased respiratory rate was noted in all animals during exposure, on removal from the chamber and one hour after removal.
- One day after exposure, all animals exhibited increased respiratory rate, hunched posture and pilo-erection. Animals recovered to appear normal from Days 8 to 10 post-exposure.
Body weight:
- Two males and two female animals exhibited slight bodyweight losses on the first day post-exposure. Reasonable bodyweight development was noted in all male animals during the remainder of the recovery period. In contrast, two female animals exhibited bodyweight losses from Days 1 to 3 post-exposure.
- Bodyweight gains were noted in all female animals for the remainder of the recovery period.
Gross pathology:
No macroscopic abnormalities were detected amongst animals at necropsy.
Other findings:
None

Table 7.2.2/1: Exposure Chamber Concentration

The test atmosphere was sampled seventeen times during the exposure period and the actual concentration of the test item calculated. The mean values obtained were:

Atmosphere Concentration

Mean Achieved (mg/L) 

Standard Deviation 

Nominal (mg/L) 

5.31

0.22

18.8

 

The chamber flow rate was maintained at 60 L/min providing 120 air changes per hour.

The theoretical chamber equilibration time (T99) was 3 minutes (Silver, 1946).

Table 7.2.2/2: Particle Size Distribution

Mean Achieved Atmosphere Concentration (mg/L)

Mean Mass Median Aerodynamic Diameter (μm)

Inhalable Fraction

(% <4 μm)

Geometric Standard Deviation

5.31

1.93

77.4

2.65

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the inhalation LC50 for ST 01 C 11 is higher than 5.31 mg/L for 4 h in rats and therefore it is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to GHS.
Executive summary:

In an acute inhalation toxicity study performed according to OECD Guideline 436, groups (3/sex/dose) of RccHanTM: WIST strain rats were exposed (nose only) to aerosol atmosphere of ST 01 C 11 at concentration of 5.31 mg/L (mean achieved) for 4 h. Animals were observed for mortality, clinical signs and body weight for 14 days and at the end of the study the animals were sacrificed for macroscopic examination.

 

No mortality was observed. Common abnormalities noted during the study included increased respiratory rate, hunched posture, pilo-erection and wet fur. Isolated occurrences of red/brown staining around the eyes or snout were also noted. Animals recovered to appear normal from Days 8 to 10 post-exposure. Two male and two female animals exhibited slight bodyweight losses on the first day post-exposure. Reasonable bodyweight development was noted in all male animals during the remainder of the recovery period. In contrast, two female animals exhibited bodyweight losses from Days 1 to 3 post-exposure. Bodyweight gains were noted in all female animals for the remainder of the recovery period. No macroscopic abnormalities were detected amongst animals at necropsy.

LC50 (4 hours) combined > 5.31 mg/L

 

Under the test conditions, the inhalation LC50 for ST 01 C 11 is higher than 5.31 mg/L for 4 h in rats and therefore it is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to GHS.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
5 310 mg/m³
Quality of whole database:
The key study is GLP compliant and of high quality (Klimisch score = 1)

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:
12-26 March 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted in compliance with OECD Guideline No. 402 without any deviation.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted 24 February 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on July 10, 2012/ signed on November 30, 2012)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK.
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 241-252 g (males); 207-216 g (females)
- Housing: Animals were housed in suspended solid-floor polypropylene cages furnished with woodflakes. Animals were housed individually during the 24 hour exposure period and in groups of five by sex for the remainder of the study
- Diet: Food (2014 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: 12-26 March 2014
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Pretreatment: On the day before treatment the back and flanks of each animal were clipped free of hair.
- Area of exposure: Back and flank area
- % coverage: Approximately 10 % of the total body surface area.
- Application of test item: Test item was used as supplied. The test item was applied as evenly as possible to an area of shorn skin (approximately 10 % of the total body surface area) using a graduated syringe.
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. The animals were caged individually for the 24 hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the 24 hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test item. The animals were returned to group housing for the remainder of the study period.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Specific gravity of test item: 0.991
- Constant volume or concentration used: Yes; 2.02 mL/kg bw
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Animals were observed for mortality or clinical signs of toxicity at 0.5, 1, 2 and 4 h after dosing and subsequently once daily for 14 days. After removal of the dressings and subsequently once daily for 14 days, the test sites were examined for evidence of primary irritation and scored according to Draize scale.
- Frequency of weighing: Individual body weights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: Yes; at the end of the study animals were killed by cervical dislocation and subjected to gross necropsy.
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.
Remarks on result:
other: no mortality was observed
Mortality:
No mortality was observed.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
- Three females showed body weight loss or no gain in body weight during the first week with expected gain in body weight during the second week.
- The remaining animals showed expected gains in body weight over the study period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
There were no signs of dermal irritation.

None

Interpretation of results:
GHS criteria not met
Conclusions:
Dermal LD50 Combined > 2000 mg/kg bw. Under the experimental conditions of this study, the test item is not classified according to Regulation (EC) No. 1272/2008 (CLP) and to GHS.
Executive summary:

In an acute dermal toxicity study (limit test) performed according to OECD Guideline No. 402 and in compliance with GLP, a group of Wistar (RccHan™:WIST) rats (5/sex) was given a single dermal application of the undiluted test item at 2000 mg/kg bw to intact skin of the back and flank area at the dose volume of 2.02 mL/kg bw. Test sites were covered with a semi-occlusive dressing for 24 h. Animals were 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. Skin irritation was assessed and scored according to the Draize scale at 24 h after removal of the dressings and then daily for 14 days.

 

No mortality, signs of dermal irritation or systemic toxicity were observed. Three females showed body weight loss or no gain in body weight during the first week with expected gain in body weight during the second week. The remaining animals showed expected gains in body weight over the study period. No abnormalities were noted at necropsy.

 

Dermal LD50 Combined > 2000 mg/kg bw

 

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

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
2 000 mg/kg bw
Quality of whole database:
The key study is GLP compliant and of high quality (Klimisch score = 1)

Additional information

Acute oral toxicity:

A key study was identified (Harlan, 2012). In this 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 sighting study, no mortality or clinical signs were observed at 300 and 2000 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 was observed at 2000 mg/kg bw. No signs of systemic toxicity were noted during the observation period. All animals showed expected gains in bodyweight over the observation period. Dark liver was noted at necropsy of one animal at 2000 mg/kg bw. No abnormalities were noted at necropsy of the remaining animals.

 

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

Acute dermal toxicity:

A key study was identified (Harlan, 2014). In this acute dermal toxicity study (limit test) performed according to OECD Guideline No. 402 and in compliance with GLP, a group of Wistar (RccHan™:WIST) rats (5/sex) was given a single dermal application of the undiluted test item at 2000 mg/kg bw to intact skin of the back and flank area at the dose volume of 2.02 mL/kg bw. Test sites were covered with a semi-occlusive dressing for 24 h. Animals were 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. Skin irritation was assessed and scored according to the Draize scale at 24 h after removal of the dressings and then daily for 14 days.

 

No mortality, signs of dermal irritation or systemic toxicity were observed.Three females showed body weight loss or no gain in body weight during the first week with expected gain in body weight during the second week. The remaining animals showed expected gains in body weight over the study period. No abnormalities were noted at necropsy.

 

Dermal LD50 Combined > 2000 mg/kg bw

Acute inhalation toxicity:

A key study was identitifed (Harlan, 2013). In this acute inhalation toxicity study performed according to OECD Guideline 436, groups (3/sex/dose) of RccHanTM: WIST strain rats were exposed (nose only) to aerosol atmosphere of ST 01 C 11 at concentration of 5.31 mg/L (mean achieved) for 4 h. Animals were observed for mortality, clinical signs and body weight for 14 days and at the end of the study the animals were sacrificed for macroscopic examination.

 

No mortality was observed. Common abnormalities noted during the study included increased respiratory rate, hunched posture, pilo-erection and wet fur. Isolated occurrences of red/brown staining around the eyes or snout were also noted. Animals recovered to appear normal from Days 8 to 10 post-exposure. Two male and two female animals exhibited slight bodyweight losses on the first day post-exposure. Reasonable bodyweight development was noted in all male animals during the remainder of the recovery period. In contrast, two female animals exhibited bodyweight losses from Days 1 to 3 post-exposure. Bodyweight gains were noted in all female animals for the remainder of the recovery period. No macroscopic abnormalities were detected amongst animals at necropsy.

LC50 (4 hours) combined > 5.31 mg/L

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 (Oral):

Based on the available information, the substance is:

- not classified according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).

Acute toxicity (Dermal):

Based on the available information, the substance is:

- not classified according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) as the dermal LD50 is higher than 2000 mg/kg bw

- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met)

Acute toxicity (Inhalation):

Based on the available information, the substance is :

- not classified according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) as the inhalation LC50 is higher than 5.31 mg/L

- not classified according to the GHS since there is no reliable evidence that indicates the LC50 to be in the range of Category 5 values (GHS criteria not met)

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.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex I of the Regulation (EC) No. 1272/2008 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 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.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex I of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute dermal toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

The classification criteria according to the Annex I of the Regulation (EC) No 1272/2008 as specific target organ toxicant (STOT) – single exposure, inhalation 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 (inhalation, dust/mist) for a Category 1 classification (C≤ 1 mg/L) and at the guidance value (inhalation, dust/mist) for a Category 2 classification (5 mg/L ≥C > 1 mg/L). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3 / H336) according to Annex I of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute inhalation toxicity study.