Registration Dossier

Administrative data

Description of key information

Acute toxicity oral route

The oral LD50 obtained in a study conducted with male and female rats according to the OECD guideline 401 is greater than 6000 mg/kg-bw.

Acute toxicity dermal route

Experimental result obtained in a study conducted according to OECD guideline 402. GLP study. The acute dermal LD50 in the Sprague-Dawley rat was greater than 2000 mg/kg-bw.

Acute toxicity inhalation route

Data waiving: In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since 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.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
other: SPF-Wistar rats, strain Winkelmann, Paderborn
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: mean body weights: 240 g for males and 215 g for females
- Fasting period before study: 16 hours before the test started, the animals were left without food.
- Housing: single cages
- Diet (e.g. ad libitum): Altromin, Lage, ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1 ºC
- Humidity (%): 50-60%
- Photoperiod (hrs dark / hrs light): 12 h dark/12 h light


Route of administration:
oral: gavage
Vehicle:
other: Tylose 0.25%
Details on oral exposure:
VEHICLE
- Concentration in vehicle: the test compound was diluted 30% in Tylose 0.25%
- Amount of vehicle (if gavage): All animals received 0.1 ml for dosage group 3000 mg/kg and 2.0 ml for dosage group 6000 mg/kg per 100 g of body weight.









Doses:
3000 and 6000 mg/kg
No. of animals per sex per dose:
4 animales per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weekly reports
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 6 000 mg/kg bw
Based on:
test mat.
Mortality:
Neither acute nor late mortalities occurred in any of the dosage groups.
Clinical signs:
The substance did not cause any remarkable symptoms which were due to the applicated compound.
Body weight:
There was no dose-related difference in weight gains after 14 days observation time.
Gross pathology:
No findings did occur in final autopsy and no pathological changes could be observed macroscopically.
Interpretation of results:
GHS criteria not met
Conclusions:
The 24 -h LD50 was greater than 6000 mg/kg bw and after 14 days no late mortalities occurred. In the test dosages the substance did not cause any remarkable symptoms. In the final autopsy no clear anatomic-pathological changes occurred.
Executive summary:

BHT was tested in an acute toxicity study after one oral application on the rat. Groups of 4 rats per sex per dose was administered doses of 3000 and 6000 mg/kg bw. The 24 -h LD50 was greater than 6000 mg/kg bw and after 14 days no late mortalities occurred. In the test dosages the substance did not cause any remarkable symptoms. In the final autopsy no clear anatomic-pathological changes occurred.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
6 000 mg/kg bw
Quality of whole database:
The key study has a high quality (Klimish score=1). There are 2 supporting studies (Klimish score= 4) which report lower dose descriptors, for quality considerations the value reported in the key study is considered the relevant dose descriptor for the endpoint.

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:
From November 12 to November 30, 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa-Credo: Les Oncins, 69210 L´Arbresle, France
- Age at study initiation: 5-7 weeks old
- Weight at study initiation: males: 197-229 g; females: 149-183 g
- Housing: Individual housing in polycarbonate cages of type FI, and of internal dimensions 305 x 180 x 184 mm
- Diet (e.g. ad libitum): Rat-mouse pelleted complete maintenance diet, ad libitum.
- Water (e.g. ad libitum): Softened and filtered drinking water, ad libitum.
- Acclimation period: Minimum of one week before the beginning of treatment.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 30-70%
- Air changes (per hr): Not documented
- Photoperiod (hrs dark / hrs light): a 12-hour light-dark cycle


IN-LIFE DATES: From November 12 to November 30, 1987
Type of coverage:
semiocclusive
Vehicle:
other: an aqueous dispersion at 10% (w/v) of gum Arabic
Details on dermal exposure:
TEST SITE
- % coverage: 10% of the total body surface area
- Type of wrap if used: The test material was held in contact with the skin with a bandage composed of a 10 cm wide adhesive and perforated tape, appied on a crimped gauze bandage covering the whole clipped area.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): The test material was wiped away by a rinsing with lukewarm water.
- Time after start of exposure:


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.8 ml/kg of live bodyweight
- For solids, paste formed: The test material being under the form of crystals was reduced into a powder in a mortar and put under the form of a paste at 71.43 % w/v in an aqueous dispersion at 10% w/v of gum Arabic.


Duration of exposure:
24 hours
Doses:
Preliminary study: 1000 and 2000 mg/kg
Definitive study: 0 and 2000 mg/kg
No. of animals per sex per dose:
Preliminary study: 2 animals per sex per dose
Definitive study: 5 animals per sex
Control animals:
yes, concurrent vehicle
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortalities and abnormal clinical signs were recorded 15 minutes after administration of the test article, then 1, 2 and 4 hours later and daily for the 14 day study period. The daily observations took into account any changes to the hair, the treated skin, the eyes, they mucous membranes, the respiratory system, the circulatory system, the autonomous and central nervous systems, motor activity and behaviour. Special attention was paid when quivering, convulsions, salivation, diarrhea, apathy, sleep and coma were observed. The animals were weighed on Day 1, Day 8 and Day 15.
- Necropsy of survivors performed: yes
- Other examinations performed: The abdominal and thoracic cavities were opened and a special observation was performed on the following organs: liver, heart, kidneys, lungs. An examination of the skin was also carried out on the application site.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
None of the rats died.
Clinical signs:
There were no clinical signs observed.
Body weight:
The treated animals showed body weights similar to the control animal body weights.
Gross pathology:
There were no macroscopic findings.
Other findings:
There were no dermal reactions.

Table 7.2.3:      Summary of Acute Dermal Toxicity

Males

Females

Dose

Mortality

Time of death

Dose

Mortality

Time of death

0 mg/kg

0/5

--

0 mg/kg

0/5

--

2000 mg/kg

0/5

--

2000 mg/kg

0/5

--

Interpretation of results:
other: Not classified according to EU criteria. Since the GHS has an additional category, the available information does not allow to determine if the subtance would be classified in category V or if the GHS criteria is not met.
Conclusions:
The acute dermal LD50 in the Sprague-Dawley rat was greater than 2000 mg/kg-bw.
Executive summary:

The test material was reduced to a powder and put under the form of a paste at 71.43 % w/v in an aqueous dispersion at 10% w/v of gum Arabic. The test material was applied to the skin of five animals per sex per dose. The acute dermal LD50 in the Sprague-Dawley rat was greater than 2000 mg/kg-bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
The key study has high quality (Klimish score=1) and its results are consistent with the supporting study which meet generally accepted scientific principles and has a good quality (Klimish score=2).

Additional information

Acute toxicity oral route

Key study: The oral LD50 obtained in a study conducted with male and female rats according to the OECD guideline 401 is greater than 6000 mg/kg-bw.

Some earlier, not well documented studies described lower LD50 values in rats (e.g. 1700 for males and 1970 mg/kg-bw for females as referenced in Deichmann et al., 1955; and 890 mg/kg as referenced in the handbook Sax, 1984). The study conducted in accordance with OECD test guidelines is considered more appropriate for this endpoint.

Some acute oral data are available in other species. However, as established in the CLP Regulation, the preferred test species for evaluation of acute toxicity by the oral route is the rat.

Acute toxicity dermal route

Key study: Experimental result obtained in a study conducted according to OECD guideline 402. GLP study. The test material was applied to the skin of five animals per sex per dose. The acute dermal LD50 in the Sprague-Dawley rat was greater than 2000 mg/kg-bw.

Acute toxicity inhalation route

Data waiving: In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since 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 classification or non-classification

Since the oral LD50 in rats is greater than 6000 mg/kg bw and the dermal LD50 is greater than 2000 mg/kg bw, the substance is not classified for acute toxicity in accordance to CLP Regulation.