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Description of key information

A study was performed for calcium titanium trioxide to evaluate potential acute toxicity via the oral route from a single dose in female Wistar Han™ (sub-strain: RccHan™: WIST) rats. The experimental results are considered to be a suitable predictor of toxicity by the oral route in humans. The study was carried out according to Good Laboratory Practise (GLP), OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method), and EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure) of Commission Regulation (EC) No. 440/2008. A fixed-dose procedure was followed and no deviation from the protocols was reported.

Administration of calcium titanium trioxide was by oral gavage at a dose volume of 10 mL/kg using arachis oil BP as a vehicle. An initial sighting test was performed to determine an initial dose level for the main test that would produce some signs of toxicity but without causing severely toxic effects or mortality. Doses levels of 300 and 2000 mg/kg were administered as part of the sighting test to a single animal per dose level investigated and all animals were observed for a minimum of fourteen days. As no mortality was observed during the sighting experiment, the main test was conducted at a dose level of 2000 mg/kg using a group of five animals.

After a 14-day observation period, no mortality was found in the group of five female rats as part of the main test. In addition, there were no signs of systemic toxicity, weight gain above that expected, nor abnormalities at necropsy. The LD50 of calcium titanium trioxide was subsequently determined to be >2000 mg/kg. The substance does not meet the criteria for classification according to Regulation 1272/2008.

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:
November 13, 2017 to December 06, 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
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
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Oxon, UK
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: 159 g to 181 g
- Fasting period before study: Food removed overnight prior to dosing and returned approximately 3 to 4 hours after dosing
- Housing: Houses in groups of up to four by sex in polypropylene cages with stainless steel mesh lids and furnished with softwood flake bedding (Datesand Ltd., Cheshire, UK)
- Diet (e.g. ad libitum): With the exception of an overnight fast immediately before dosing and for approximately 3 to 4 hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK) was allowed throughout the study.
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 to 70 %
- Air changes (per hr): At least fifteen air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours of continuous artificial light and 12 hours of darkness in each 24-hour period
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: Concentration: 200 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

DOSAGE PREPARATION: The test item was formulated within 2 hours of being applied to the test system. It is assumed that the formulation was stable for this duration. No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement.
Doses:
Dose levels of 300 and 2000 mg/kg were used in an initial sighting test. When no signs of toxicity were observed at the initial dose, the following higher dose level was investigated. Dosing was sequential, allowing sufficient time between each dose group to confirm the survival of the previously dosed animal before investigation of the next dose level. In the main experiment, an initial dose level of 2000 mg/kg was selected as this dose was determined to be likely to produce evident toxicity but no compound-related mortality (including humane kills).
No. of animals per sex per dose:
A single animal was used for each dose level investigated in the sighting test and in the main test, a group of five animals used for the dose level investigated. The five animals consisted of one animal from the sighting test dosed at the selected dose level together with an additional four animals.
Control animals:
no
Details on study design:
- Duration of observation period following administration: Fourteen days
- Frequency of observations: Morbidity / mortality inspection occurred twice daily, early and late, during a normal working day and once daily at weekends and public holidays.
- Necropsy of survivors performed: Necropsy was carried out on all animals that died or were humanely killed during the study (by cervical dislocation) and on all survivors humanely killed on day 14 or at the end of the study. Organs were examined for macroscopic abnormalities.
- Other examinations performed: Body weights were recorded on day 0 (prior to dosing), 7, and 14, or at death. Clinical observations were performed 30 minutes and 1, 2, and 4 hours after dosing, then at least once daily for 14 days. Observations included potential changes in the skin and fur; eyes and mucous membranes; respiratory, circulatory, autonomic and central nervous system; somatomotor activity; and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep, and coma.
Statistics:
The computerised system: Delta Controls - ORCAview (v3.4.0), was used in the study.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths were observed.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
The animal showed an expected gain in body weight over the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
Following an acute oral toxicity experiment in rats, it was determined that calcium titanium trioxide was not acutely toxic via the oral route under the conditions of the study. No mortality was observed at the highest dose over a 14-day period, rendering an LD50 >2000 mg/kg bw. The substance does not meet the criteria for classification according to Regulation 1272/2008.
Executive summary:

A study was performed for calcium titanium trioxide to evaluate potential acute toxicity via the oral route from a single dose in female Wistar Han™ (sub-strain: RccHan™: WIST) rats. The experimental results are considered to be a suitable predictor of toxicity by the oral route in humans. The study was carried out according to Good Laboratory Practise (GLP), OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method), and EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure) of Commission Regulation (EC) No. 440/2008. A fixed-dose procedure was followed and no deviation from the protocols was reported.

Administration of calcium titanium trioxide was by oral gavage at a dose volume of 10 mL/kg using arachis oil BP as a vehicle. An initial sighting test was performed to determine an initial dose level for the main test that would produce some signs of toxicity but without causing severely toxic effects or mortality. Doses levels of 300 and 2000 mg/kg were administered as part of the sighting test to a single animal per dose level investigated and all animals were observed for a minimum of fourteen days. As no mortality was observed during the sighting experiment, the main test was conducted at a dose level of 2000 mg/kg using a group of five animals.

After a 14-day observation period, no mortality was found in the group of five female rats as part of the main test. In addition, there were no signs of systemic toxicity, weight gain above that expected, nor abnormalities at necropsy. The LD50 of calcium titanium trioxide was subsequently determined to be >2000 mg/kg. The substance does not meet the criteria for classification according to Regulation 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The LD50 of calcium titanium trioxide was subsequently determined to be >2000 mg/kg. The substance does not meet the criteria for classification according to Regulation 1272/2008.

It was not required to investigate the acute toxicity of the substance via the inhalation and dermal routes in accordance with Annex VII of REACH.