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Diss Factsheets

Administrative data

Description of key information

Oral

Under the conditions of this study, the LD50 of the test material in female rat lies between 300 and 2000 mg/kg bodyweight.

Dermal

Under the conditions of the study, the LD50 has been determined to be greater than 2000 mg/kg in the rat.  

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:
01 June 2005 to 29 June 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2004
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: Sprague-Dawley Rj: SD (IOPS Han)
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Approximately 8 weeks old
- Weight at study initiation: Animals had a mean body weight ± standard deviation of 195 ± 9 g (184 - 210 g)
- Fasting period before study: Animals were fasted for an overnight period of approximately 18 hours before dosing and for a further 4 hours post dose. Water was always freely available.
- Housing: The animals were housed in polycarbonate cages with stainless steel lid (48 x 27 x 20 cm). Each cage contained one to seven animals during the acclimation period and three rats of the same group during the treatment period. Each cage contained autoclaved sawdust.
- Diet: ad libitum. All the animals had free access to adapted pelleted diet
- Water: Drinking water filtered by an FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: At least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 30 to 70 % (relative)
- Air changes: approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod: 12 hour light/12 hour dark cycles

IN-LIFE DATES: Not reported
Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
0.5 %
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): The volume administered to each animal was adjusted according to body weight determined on the day of treatment.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The test material preparation was made extemporaneously under nitrogen atmosphere. The preparations were maintained under agitation during all the treatment period.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: As no information on the toxic potential of the test material was available, for animal welfare reasons, the starting dose-level of 300 mg/kg was chosen. After the first assay, as no deaths occurred, another assay was carried out on three animals at the next higher dose-level, i.e. 2000 mg/kg. After the second assay, as all animals died, the result obtained at the dose-level of 300 mg/kg were confirmed on another group of three animals.
Doses:
300 and 2000 mg/kg
No. of animals per sex per dose:
3 animals per dose group; two groups dosed at 300 mg/kg and one group dosed at 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days.
- Frequency of observations and weighing: The animals were observed frequently during the hours following administration of the test material, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day. The animals were weighed individually just before administration of the test material on day 1 and then on days 8 and 15. For the animals that died, time of death was recorded individually, in terms of the number of hours or days after dosing.
- Necropsy of survivors performed: Yes. On day 15, all surviving animals were killed by carbon dioxide asphyxiation. All study animals were subjected to a macroscopic examination as soon as possible after death. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
- Dose-level of 300 mg/kg (three females then confirmation on three other females): No mortality was observed during the study.
- Dose-level of 2000 mg/kg (three females): All animals died within 2 hours of treatment.
Clinical signs:
- Dose-level of 300 mg/kg (three females then confirmation on three other females): No clinical signs were observed during the study.
- Dose-level of 2000 mg/kg (three females): Hypoactivity and tremors were observed prior to the death of the animals.
Body weight:
Dose-level of 300 mg/kg: Although the animals gained weight, the weight gain of 2/6 animals was slightly reduced during the second week of the study when compared to historical control animals. The body weight gain of the other animals was not considered to be affected by treatment with the test material.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Interpretation of results:
other: Classified as Category 4 in accordance with EU criteria
Conclusions:
Under the conditions of this study, the LD50 of the test material in female rat lies between 300 and 2000 mg/kg bodyweight.
Executive summary:

The acute oral toxicity potential of the test material was assessed in the Sprague-Dawley rat in accordance with the standardised guidelines OECD 423 and EU Method B.1 tris under GLP conditions using the acute toxic class method.

The test material was prepared in 0.5 % methylcellulose and was administered by gavage at a dose volume of 10 mL/kg to three groups of three fasted female rats. As no information on the toxic potential of the test material was available, for animal welfare reasons the starting dose-level of 300 mg/kg was chosen. As no deaths occurred at this dose level, another assay was carried out on three animals at the next higher dose-level (2000 mg/kg). After the second assay, as all animals died, the results obtained at the dose-level of 300 mg/kg were confirmed on another group of three animals. The animals were weighed individually just before administration of the test material on day 1 and then on days 8 and 15. The animals were observed frequently during the hours following administration of the test material and daily throughout the observation period.

At 300 mg/kg (three females then confirmation on three other females) no clinical signs and no mortality were observed during the study. The body weight gain of 2/6 animals was slightly reduced during the second week of the study when compared to historical control animals. The body weight gain of the other animals was not considered to be affected by treatment with the test material.

At 2000 mg/kg (three females) all animals died within 2 hours of treatment. Hypoactivity and tremors were observed prior to the death of the animals.

At necropsy, no apparent abnormalities were observed in any animal.

Under the conditions of this study, the LD50 of the test material in female rat lies between 300 and 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 mg/kg bw
Quality of whole database:
A single study conducted in accordance with standardised guidelines and under GLP conditions is available. The quality of the database is therefore considered to be acceptable for risk assessment.

Acute toxicity: via inhalation route

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:
08 June 2005 to 22 June 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
1992
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: Sprague-Dawley Rj: SD (IOPS Han)
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Approximately 8 weeks old
- Weight at study initiation: Animals had a mean body weight ± standard deviation of 347 ± 7 g for the males and 217 ± 6 g for the females.
- Fasting period before study: No
- Housing: The animals were housed in polycarbonate cages with stainless steel lid (48 x 27 x 20 cm). Each cage contained one to seven animals of the same sex during the acclimation period and a single rat during the treatment period. Each cage contained autoclaved sawdust.
- Diet: ad libitum. All the animals had free access to adapted pelleted diet
- Water: Drinking water filtered by an FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: At least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 30 to 70 % (relative)
- Air changes: approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod: 12 hour light/12 hour dark cycles

IN-LIFE DATES: Not reported
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorsal area of each animal. On the day before treatment, the dorsal area of each animal was clipped using an electric clipper. Only animals with healthy intact skin were used for the study.
- % coverage: Approximately 10 % of the total body surface of the animals (approximately 5 x 7 cm for males and 5 x 6 cm for females)
- Type of wrap if used: The test material and the gauze pad were held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage. This dressing prevented ingestion of the test material by the animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): None. On removal of the dressing, any residual test material was removed using a dry cotton pad.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- For solids, paste formed: No; the test material was placed on a hydrophilic gauze pad (pre-moistened with 2 mL of purified water)
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days.
- Frequency of observations and weighing: The animals were observed frequently during the hours following administration of the test material, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day until day 15. From day 2 any local cutaneous reaction was recorded. The animals were weighed individually just before administration of the test material on day 1 and then on days 8 and 15.
- Necropsy of survivors performed: Yes. On day 15, all surviving animals were killed by carbon dioxide asphyxiation. All study animals were subjected to a macroscopic examination as soon as possible after death. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
No deaths occurred during the study.
Clinical signs:
Piloerection was observed in all animals within 1 hour of treatment. No more clinical signs were noted thereafter, until the end of the observation period (day 15).
No cutaneous reactions were observed during the study.
Body weight:
The body weight gain of the treated animals was similar to that of historical control animals.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
Under the conditions of the study, the LD50 has been determined to be greater than 2000 mg/kg in the rat.
Executive summary:

A study was conducted to investigate the acute dermal toxicity potential of the test material in accordance with the standardised guidelines OECD 402 and EU Method B.3 under GLP conditions.

The test material in its original form was applied to the clipped skin on the dorsal area of one group of ten Sprague-Dawley rats (five males and five females). The application was performed with a limit dose of 2000mg/kg. The test site was then covered by a semi-occlusive dressing for 24 hours. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application of the test material. At the end of the 14 day treatment period, all animals were subjected to necropsy.

No deaths were observed during the study. Piloerection was observed in all animals within 1 hour of treatment. No more clinical signs were noted thereafter, until the end of the observation period (day 15). No cutaneous reactions were observed during the study. The overall body weight gain of the animals was not considered to be affected by treatment with the test material. No apparent abnormalities were observed at necropsy in any animal.

Under the conditions of the study, the LD50 has been determined to be greater than 2000 mg/kg in the rat.  

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
A single study conducted in accordance with standardised guidelines and under GLP conditions is available. The quality of the database is therefore considered to be acceptable for risk assessment.

Additional information

Acute oral toxicity

The acute oral toxicity potential of the test material was assessed in the Sprague-Dawley rat in accordance with the standardised guidelines OECD 423 and EU Method B.1 tris under GLP conditions using the acute toxic class method. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997). 

The test material was prepared in 0.5 % methylcellulose and was administered by gavage at a dose volume of 10 mL/kg to three groups of three fasted female rats. As no information on the toxic potential of the test material was available, for animal welfare reasons the starting dose-level of 300 mg/kg was chosen. As no deaths occurred at this dose level, another assay was carried out on three animals at the next higher dose-level (2000 mg/kg). After the second assay, as all animals died, the results obtained at the dose-level of 300 mg/kg were confirmed on another group of three animals. The animals were weighed individually just before administration of the test material on day 1 and then on days 8 and 15. The animals were observed frequently during the hours following administration of the test material and daily throughout the observation period.

At 300 mg/kg (three females then confirmation on three other females) no clinical signs and no mortality were observed during the study. The body weight gain of 2/6 animals was slightly reduced during the second week of the study when compared to historical control animals. The body weight gain of the other animals was not considered to be affected by treatment with the test material.

At 2000 mg/kg (three females) all animals died within 2 hours of treatment. Hypoactivity and tremors were observed prior to the death of the animals.

At necropsy, no apparent abnormalities were observed in any animal.

Under the conditions of this study, the LD50 of the test material in female rat lies between 300 and 2000 mg/kg bodyweight.

Acute dermal toxicity

A study was conducted to investigate the acute dermal toxicity potential of the test material in accordance with the standardised guidelines OECD 402 and EU Method B.3 under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997). 

The test material in its original form was applied to the clipped skin on the dorsal area of one group of ten Sprague-Dawley rats (five males and five females). The application was performed with a limit dose of 2000mg/kg. The test site was then covered by a semi-occlusive dressing for 24 hours. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application of the test material. At the end of the 14 day treatment period, all animals were subjected to necropsy.

No deaths were observed during the study. Piloerection was observed in all animals within 1 hour of treatment. No more clinical signs were noted thereafter, until the end of the observation period (day 15). No cutaneous reactions were observed during the study. The overall body weight gain of the animals was not considered to be affected by treatment with the test material. No apparent abnormalities were observed at necropsy in any animal.

Under the conditions of the study, the LD50 has been determined to be greater than 2000 mg/kg in the rat.  

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance requires classification with respect to acute toxicity via the oral route as Category 4 (H302; Harmful if swallowed).

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to acute toxicity via the dermal route.