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Description of key information

In two acute oral toxicity studies LD50 values >2000 mg/kg bw are reported. Two acute dermal toxicity studies in the rat also resulted in LD50 values >2000 mg/kg bw.

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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
BASF-Test: The study was conducted according to an internal BASF method which in principle is comparable to the OECD Guideline 401.
A test group consisting of 5 animals/sex was treated by single gavage with an aqueous solution of the test substance and the application volume was 10 mL/kg bw.
The animals were observed for mortality and for clinical symptoms of toxicity. They were weighed prior treatment and on day 7 and 13 post-treatment. At the end of the observation period of 14 days, the surviving animals were sacrificed for the purpose of necropsy; animals that died during the observations period also were subjected to necropsy.

The LD50 value was estimated on the basis of the observed mortalities.
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. K Thomae GmbH, Biberach, D
- Mean body weight at test initiaton: 176 g (males), 180 g (females)
- Housing: 5/ cage (stainless steel wire mesh cages)
- Diet (e.g. ad libitum): Kliba Labordiaet 343
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20%
- Amount of vehicle (if gavage): 10 mL/kg b.w.
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Recording of signs and symptoms at least once each workday. Check for moribund and dead animals twice each work day. Weekly weighing.
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: 1% significance level
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Mortality:
none
Clinical signs:
no abnormalities
Body weight:
The mean male body weight increased from 176 g at d0 to 247 g at d7 and 282 g at d13.
The mean female body weight increased from 180 g at d0 to 213 g at d7 and 228 g at d13.
Gross pathology:
No pathological findings noted.
Interpretation of results:
GHS criteria not met
Conclusions:
No classification according to GHS criteria
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 23 OCT 1985 to 7 NOV 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Lot No.: 141284
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, St Germain sur l'Arbresle, France
- Weight at study initiation: males (mean): 124 g; females (mean): 120 g
- Fasting period before study: 18 h
- Housing: 5 animals/sex/cage in fully conditioned rooms
- Diet: standard rat diet of Ref. A04C (U.A.R, Villemoisson sur Orge, France), ad libitum
- Water: flitered water (Millipore membrane 0.22 µm), ad libitum
- information on diet testing dealing with contaminants were given by provider with each lot; water was tested regularly on bacterial contamination
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20+/-3
- Humidity (%): 50+/-20
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
5 ml/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: several times in the hours following the application, at least once daily during the 14 day observation period
- Frequency of weighing: just before application and then on day 4, day 8 and day 15
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 mL/kg bw
Based on:
test mat.
Remarks on result:
other: no animals died during the 14 day observation period, corresponding to 6150 mg/kg bw (density set 1.23 g/cm³), corresponding to 4305 mg submission substance per kg bw
Mortality:
- no deaths occured
Clinical signs:
- all animals were sedated within the first 30min up to about 3 h
- from 3 hours post apllication until the end of the study no more clinical signs were observed
Body weight:
- body weight development was not impaired
Gross pathology:
- no macroscopically visible changes were linked to the substance treatment
Other findings:
- Histopathology: was not performed due to the fact that there were no macroscopically visible changes
Interpretation of results:
GHS criteria not met
Conclusions:
Single application of a limit dose of 5 mL of test substance per kg bw did not cause lethality in male and female Wistar rats during the 14 day observation period, thus resulting in a LD50 > 5 mL/kg bw (corresponding to 6150 mg test item/kg bw based on a density of 1.23 g/cm³ (i.e. 4305 mg submission substance per kg bw)).
Executive summary:

Male and female Wistar rats (5/sex) were subjected to test acute oral toxicity according to a standard acute method (EU method B1). The test material was administered by gavage at a limit dose of 5 mL/kg bw. Besides some minor effects occurring after application (transient sedation in between 0.5 and 3 hours post application) no other clinical effects were seen. No animal died during the 14 day observation period, resulting in a LD50 > 5 mL/kg bw (corresponding to 6150 mg test item/kg bw based on a density of 1.23 g/cm³ (i.e. based on the concentration of 70% of the submission substance in the test item: 4305 mg submission substance per kg bw)). Therefore, the substance has not to be classified for acute oral toxicity according to regulation (EC) No. 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
4 305 mg/kg bw

Acute toxicity: via inhalation route

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:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: 000161MCA0
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Sulzfeld, Germany
- Age at study initiation: male: 8 weeks; female: 12 weeks
- Housing: single housing
- Diet (e.g. ad libitum): VRF 1(P); SDS Sepecial Diets Service (Altrip) Germany
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 26
- Humidity (%): 20 - 80
- Photoperiod (hrs dark / hrs light): 12/12


Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: 40 cm²
- % coverage: 10

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24 hours


Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Other examinations performed: clinical signs, body weight
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality occurred.
Clinical signs:
No systemic clinical signs were observed during clinical examination.
Body weight:
The mean body weight of the male animals increased within the normal range throughout the study period. Mean body weight of the female animals decreased during the first post-exposure observation week, probably due to the bandage procedure, but increased during the second week within the normal range.
Gross pathology:
No abnormalities were noted.
Other findings:
Slightly yellowish discoloration of the application site was observed on study day 1 until study day 8 in all animals after application. No local effects were observed.
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 04 MAY 2010 to 25 MAY 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Name of the test material (as cited in the report): Arkofix RCH
- Batch No.of test material: OP1
- Expiration date of the lot/batch: 16-Oct-2014
- Certificate of analysis: N° 1873, 15/04/2010

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Stability of Test Item: Stable under storage conditions
- Stability of Test Item Dilution: Stable in water
- Storage Conditions: At room temperature (range of 20 ± 5 °C, provided by Harlan Laboratories Ltd.), light protected.
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories B.V., Kreuzelweg 53, 5961 Horst / The Netherlands
- Age when treated: males: 19 weeks, females: 11 weeks
- Body weight when treated: 298.7 - 376.7 g (males), 197.0 - 208.8 g (females)
- Housing: During acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makrolon type-3 cages with standard softwood bedding (Lignocel, J. Rettenmaier&Söhne GmbH&CoKG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) during treatment and observation. Paper enrichment, Reference no. 207057, batch no. 69, (Enviro-dri from Lillico, Biotechnology, Surrey / UK) was included.
-Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 83/09 (Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) ad libitum.
- Water: Community tap water from Füllinsdorf ad libitum.
Acclimatization period: 04-May-2010 to 10-May-2010

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: between 30 - 70%
- Air changes:10 - 15 air changes per hour
- Photoperiod: 12 hours light and 12 hours dark
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: approx. 25 cm²
- Approximately 10% of the total body surface
-Type of wrap: semi-occlusive dressing wrapped around the trunk and fixed with an elastic adhesive bandage

REMOVAL OF THE TEST MATERIAL
Twenty-four hours after the application the dressing was removed and the skin was flushed with lukewarm tap water and drapped off with disposable paper towels.
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 (see table 1)
Control animals:
not required
Details on study design:
One day before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10% of the total body surface.
Only those animals without injury or irritation on the skin were used in the test.

On test day 1, the test item was applied at a dose of 2000 mg/kg body weight evenly on the intact skin with a syringe and covered with a semi-occlusive dressing. The dressing was wrapped around the trunk and fixed with an elastic adhesive bandage.

The application volume was 4 mL/kg.
Twenty-four hours after the application the dressing was removed and the skin was flushed with lukewarm tap water and drapped off with disposable paper towels. Thereafter, the reaction sites were assessed.

All animals were re-shaved on test day 8 to facilitate the reading of the local reactions.

- Duration of observation period following the administration: 15 days
- frequency of observation and weighing:
Viability / Mortality: Daily during the acclimatization period. Once before treatment, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
Clinical Signs: Daily during the acclimatization period. Once before treatment, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15.
Local Dermal Signs: Once daily during days 2 (following dressing removal) through day 15. Scoring according to the Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), B.4 ACUTE TOXICITY: DERMAL IRRITATION/CORROSION (Official Journal No L 142, 31/05/2008 p. 0182-0190.
Body Weights: On test days 1 (prior to administration), 8 and 15.
Necropsy: all 5 males and 5 females

Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No deaths occurred during the course of the study.
Clinical signs:
No clinical signs were observed throughout the entire observation period.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Other findings:
The test item caused slight to moderate yellow staining of the treated skin in four males and two females throughout the observation period.
Interpretation of results:
GHS criteria not met
Conclusions:
The median lethal dose of the test item after single dermal administration to rats of both sexes, observed over a period of 14 days, is:
LD50 (rat): greater than 2000 mg/kg body weight
Executive summary:

Five male and five female RccHan:WIST (SPF) rats were treated with test item at 2000 mg/kg by dermal application. The test item was formulated in purified water at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg. The application period was 24 hours.
 
The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs before treatment, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded before treatment, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.
 
No deaths occurred during the study.
 
No clinical signs were observed during the course of the study.
 
The test item caused slight to moderate yellow staining of the treated skin in four males and two females throughout the observation period.
 
The body weight of the animals was within the range commonly recorded for this strain and age.
 
No macroscopic findings were observed at necropsy.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

Acute toxicity via oral route

Male and female Wistar rats (5/sex) were subjected to test acute oral toxicity according to a standard acute method (EU method B1; Clariant, 1793TAR, 1986). The test material was administered by gavage at a limit dose of 5 mL/kg bw. Besides some minor effects occurring after application (transient sedation in between 0.5 and 3 hours post application) no other clinical effects were seen. No animal died during the 14 day observation period, resulting in a LD50 > 5 mL/kg bw (corresponding to 6150 mg/kg bw based on a density of 1.23 g/cm³ (i.e. 4305 mg submission substance per kg bw).

In a supportive study, comparable to OECD guideline 401, male and female rats were exposed to a dose of 2000 mg/kg bw of the test substance by gavage (BASF, 10A1019/881235, 1989). No animal died during the test and there were no signs of toxicity. The LD50 was determined to be >2000 mg/kg bw.

Acute toxicity via dermal route 
Five male and five female RccHan:WIST (SPF) rats were tested in an acute dermal toxicity study according to standard acute method (EU method B3, OECD 402; Clariant, C92388, 2010). The test item was formulated in purified water at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg (i.e. dermal application of limit dose of 2000 mg/kg bw). The application period was 24 hours under semi-occlusive conditions.
No deaths occurred and no clinical signs were observed during the study. The test item caused slight to moderate yellow staining of the treated skin in four males and two females throughout the observation period. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy. Based on these observations the LD50 for dermal acute toxicity is > 2000 mg/kg bw.

In a supportive study, according to OECD guideline 402, groups of 5 Wistar rats per sex were dermally exposed to a dose of 2000 mg/kg bw of the test substance (BASF, 11A0300/099071, 2009). The application periode was 24 hours under semi-occlusive conditions. No mortality occurred during the test and no systemic clinical, signs were observed. Slightly yellowish discoloration of the application site was observed on study day 1 until study day 8 in all animals after application. No local effects were observed. The determined LD50 was >2000 mg/kg bw.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on acute toxicity, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.