Magnesium potassium titanium oxide

Endpoint summary

Description of key information

Acute oral toxicity study with Terracess P (EC B.1, OECD 423): LD50 > 2000 mg/kg bw (rat).
Acute dermal toxicty (OECD 402, non-GLP) study with Terracess P (OECD 402): LD50> 2000 mg/kg bw (rat)
Acute inhalation study with Terracess P (OECD 403): LC50 > 5.04 mg/L air (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:

31 October 2000-16 November 2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study has been performed according to OECD and EC guidelines and according to GLP principles.

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

(1996)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

(1996)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Wistar strain Crl:(WI) BR (outbred, SPF-Quality)

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River Deutschland, Sulzfeld, Germany
- Males/females. Females were nulliparous and non-pregnant.
- Age at study initiation: Young adult animals (approx. 11 weeks old).
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean
- Housing: Group housing of 3 animals per sex per cage in labelled polycarbonate cages (Macrolon, type IV; height 15 cm.) containing purified sawdust as bedding material (SAWI, Jelu Werk, Rosenberg, Germany)
- Free access to standard pelleted laboratory animal diet (Altromin (code VRF 1), Lage, Germany)
- Free access to tap water
- The acclimation period was at least 5 days before the start of treatment under laboratory conditions.
- A health inspection was performed prior to commencement of treatment, to ensure that the animals were in a good state of health.

Results of analysis for diet (nutrients and contaminants), sawdust and water were assessed and did not reveal any findings that were considered to have affected the study integrity. All certificates and results of analysis are retained in the NOTOX archives.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±3ºC
- Humidity (%): 30 - 70%
- Air changes (per hr): approximately 15 air changes per hour- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day.

Route of administration:

oral: gavage

Vehicle:

other: 1% Aqueous carboxymethyl cellulose.

Details on oral exposure:

GAVAGE METHOD: stainless steel stomach tube.

FREQUENCY: single dosage, on Day 1.

VEHICLE : 1% Aqueous carboxymethyl cellulose
The vehicle was selected based on a pretest performed at NOTOX

DOSAGE PREPARATION: The formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level.

Doses:

2000 mg/kg (10 mL/kg) body weight.

No. of animals per sex per dose:

3 males and 3 females.

Control animals:

no

Details on study design:

Animals were deprived of food overnight prior to dosing (max. 20 h) and until 3-4 hours after administration of the test substance. Water was available ad libitum.

OBSERVATION
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: twice daily
Body weight: Day 1 (pre-administration), 8 and 15
- Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded.
- Necropsy of survivors performed: At the end of the observation period, all animals were sacrificed by asphyxiation using an oxygen/carbon dioxide procedure and subjected to necropsy
- Other examinations performed: none.

Statistics:

No statistical analysis was performed (the method used is not intended to allow the calculation of a precise LD50 value).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: No clinical signs of toxicity were noted.

Gross pathology:

Effects on organs: Reduced size of testes was observed in one male. No abnormalities were found at macroscopic post mortem examination of the other anaimals.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral LD50 of Terracess P in rat is > 2000 mg/kg bw.
Terracess P does not have to be classified and has no obligatory labelling requirement for oral toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study has a Klimisch score of 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:

09-23 February 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study has been performed according to OECD and EC guidelines and according to GLP principles.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

(1997)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Wistar, SPF-reared, Wistar derived (Crl:[WI]WU BR)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS (5 males/5 females)
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: 6 weeks (before acclimatisation)
- Weight at study initiation: the mean body weights of the rats were 321 g and 200 g for male and female animals, resp., just before exposure.
- Earmark for identification
- Housing: Conventional conditions in suspended stainless steel cages fitted with wire-mesh floor and front
- Diet: a commercially available rodent diet (Rat & Mouse No. 3 Breeding Diet RM3) from SDS Special Diets Services, Witham, England).
- Water: Tap water suitable for human consumption.
- Acclimation period: 36 days
- No access to feed or water during exposure.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): between 19.0 and 22.0°C
- Humidity (%): between 40 and 66%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: none

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Exposure in a nose-only inhalation chamber, a modification of the chamber manufactured by ADG developments Ltd., Codicote, Hitchin, Herts. SG4 8 UB, United Kingdom. The inhalation chamber consisted of a cylindrical aluminium column, surrounded by a transparent cylinder. The column had a volume of ca. 50L and consisted of a top assembly with two mixing chambers, underneath a rodent tube section and the exhaust section at the bottom. The rodent tube section had 20 ports for animal exposure. Empty ports were closed if not used for test atmosphere sampling, particle size analysis, measurement of oxygen concentration, temperature and relative humidity.

The animals were secured in plastic animal holders (Batelle), positioned radially through the outer cylinder around the central column. Male and female rats of each group were placed in alternating order. Only the nose of the rat protruded into the interior of the column. By securing a positive pressure in the central column and a slightly negative pressure in the outer cylinder, which encloses the entire animal holder, air leaks from nose to thorax rather than from thorax to nose and dilution of test atmosphere at the nose of the animals is prevented.

The inhalation equipment was designed to expose rats to a continuous supply of fresh test atmosphere. The test atmosphere was generated by passing test material to an eductor (Fox mini, type 060, Spraybest Europe BV, Zwanenburg, the Netherlands) using a dry material feeder (Gericke GMD 60, Gericke AG, Regensburg, Switzerland). The eductor was placed at the inlet of the exposure unit and was operated with pressurized dry air controlled by a pressure reducing valve at 0.5 bar. The test material was delivered in a slip stream of humidified air. The resulting aerosol was directed downwards towards the animal noses. At the bottom of the unit the test atmosphere was exhausted. The mean flow of air was 84.8 L/min. The period between the start of the generation of the test atmosphere and the start of exposure of animals was 135 minutes.

TEST ATMOSPHERE
The concentration of the aerosol in the test atmosphere was determined once per hour by gravimetric analysis. During exposure, representative samples were obtained by passing 5 L test atmosphere samples at 5 L/min through glass fibre filters (Sartorius, 13430-44-5). Filters were weighed before sampling, loaded with aerosol particles and weighed again.

Particle size distribution measurement was carried out once in the preliminary phase and once during exposure using a 10-stage cascade impactor (Anderson, Atlanta, USA) with the largest cut-off size of 32 µm.


Temperature (21.5 +/- 0.1°C) and humidity (44 +/-1%) in air chamber were recorded eight times during exposure at regular intervals (ca. twice per hour) using an RH/T device (TESTO 610, TESTO GmbH & Co, Lenzkirch, Schwarzwald, Germany) . The oxygen concentration was checked once during exposure (Beryl, Cosma, Igny, France): 21.6%.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

by gravimetric analysis

Duration of exposure:

4 h

Concentrations:

The measured aerosol concentrations during exposure were 5.298, 4.806, 4.944, 5.022, 5.162 and 5.016 g/m3.
Mean: 5.04 +/- 0.17 g/m3 (n=6).

The nominal concentration was calculated by dividing the total amount of test material used (by calculating the yield of the feeder allowing for the adjustment of its settings) by the total volume of air passed through the exposure unit: 9.4 g/m3.

The generation efficiency was 54% (a common value).

No. of animals per sex per dose:

One group of 5 male and 5 female rats

Control animals:

no

Details on study design:

- Duration of observation period following exposure: 14 days
- Visual inspection of the rats (for behaviour, clinical signs and mortality) just before exposure, shortly after exposure and at least once daily during the observation period.
- Body weights were recorded just before exposure (day 0), on day 7 and on day 14
- Necropsy of survivors performed: yes (at the end of the 14-day observation period)
- All rats were examined for gross pathological changes

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.04 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Males: 0/5
Female: 0/5

Clinical signs:

other: A slightly decreased breathing rate was seen in all animals during exposure. In a few animals (1 male and 2 female rats) slight laboured breathing was seen in the last two hours during exposure. Shortly after exposure or during the 14-day observation

Body weight:

Overall body weight gain in the animals was considered normal for rats of this strain and age.

Gross pathology:

Exposure related abnormalities were not found at necropsy.

Other findings:

During the 14-day observation period, treatment related abnormalities were not observed.

It was shown that 76% of the mass of the aerosol present at the animals' breathing zone was contained in particles with an aerodynamic diameter equal to or smaller than 5 um

The Mass Median Aerodynamic Diameter (MMAD) = 3.1 µm. The Geometric standard deviation = 1.8. (in preliminary experiment: MMAD = 3.0 µm. Geometric standard deviation = 1.6)

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute inhalation 4h-LC50 of Terracess P is > 5.04 mg/L air (rat)
TERRACESS P does not have to be classified and has no obligatory labelling requirement for inhalation toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5.04 mg/m³ air

Quality of whole database:

The study has a Klimisch score of 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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Not performed according to GLP principles.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

(1987)

Deviations:

not specified

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

female

Vehicle:

corn oil

Duration of exposure:

24 h

Doses:

0 (control) and 2000 mg/kg

No. of animals per sex per dose:

5 animals in each group

Control animals:

yes, concurrent vehicle

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations daily. weighing on day 1, 2, 3, 7, 10 and 14.
- Necropsy of survivors performed: yes on day 14
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality

Clinical signs:

other: No clinical signs

Gross pathology:

No abnormalities

Other findings:

None

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral LD 50 of Terracess P in rats was > 2000 mg/kg body weight.
Terracess P does not have to be classified and has no obligatory labelling requirement for dermal toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study has a Klimisch score of 2. Not performed according to GLP principles.

Additional information

Oral toxicity

According OECD 423 and EC B.1 test guidelines, Terracess P was administered by oral gavage to three female and three male Wistar rats at 2000 mg/kg body weight. No mortality occurred, no clinical signs were noted, and the body weight gain shown by the animals over the study period was considered to be normal. No abnormalities were found at macroscopic post mortem examination of the animals, except a reduced size of testes was observed in one male. The oral LD50 value of Terracess P in Wistar rats was established to exceed 2000 mg/kg bw.

Dermal toxicity

In a non-GLP OECD 402 test guideline study, Terracess P was administered dermally to five females at 200 mg/kg bw for 24 hours. No mortality, effects or abnormalities were observed at the concentration of 2000 mg/kg bw in the acute dermal test and thus the dermal LD50 exceeds 2000 mg/kg bw. Furthermore, the properties of Terracess P (very low water solubility) suggest a low dermal absorption through the skin.

Inhalation toxicity

According to the OECD 403 test guideline, Terracess P was administered by inhalation for 4 hours (nose-only) to one group of five male and five female Wistar rats.The mean actual concentration was 5.04 ± 0.5 mg/L. The MMAD of the particles in the aerosol was 3.1µm (gsd 1.8).

No mortalities occurred. During exposure, a slight decreased breathing rate was seen in all animals at all observation times. In a few animals slight laboured breathing was seen in the last two hours during exposure. Shortly after exposure or during the 14 -d observation period no abnormalities were seen. Overall body weight gain in the animals was within the range expected for rats of this strain and age used in this type of study. No abnormalities were found at macroscopic post mortem examination of the animals.The inhalatory 4 -h LC50 value of Terracess P in Wistar rats was established to exceed 5 mg/l.

Justification for selection of acute toxicity – oral endpoint
One key study available.

Justification for selection of acute toxicity – inhalation endpoint
One key study available.

Justification for selection of acute toxicity – dermal endpoint
One key study available.

Justification for classification or non-classification

Based on the available studies, Terracess P does not have to be classified for acute toxicity according to Directive 67/548/EEC and CLP Regulation EC (No.) 1272/2008.