Chrome tungsten titanium buff rutile

Endpoint summary

Description of key information

oral
LD50 rat > 5000 mg/kg bw

dermal
not relevant

inhalation
LC50 > 5.08 mg/L for both sexes (MMAD: 1.257µm (GSD: 3.368))

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:

2021-08-05 to 2021-08-2021

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:

2001-12-17

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 2020-11-06.

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at + 10 to +25 °C, keep dry in closed containers.

Species:

rat

Strain:

Crj: CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 9 weeks
- Weight at study initiation: 183 - 186 g
- Fasting period before study: yes, approximately 16 hours before administration.
- Housing: during the 14-day observation period the animals were kept in groups of 3 animals in MAKROLON cages (type III plus); bedding material: granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany).
- Diet (ad libitum): commercial diet, ssniff® R/M-H V1534 (supplier: ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum): tap water
- Acclimation period: at least 14 adaptation days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C ± 3 °C
- Humidity: 55 % ± 10 %
- Photoperiod (hrs dark / hrs light): 12 / 12; rooms were lit (about 150 lux at approx. 1.50 m room height).

Route of administration:

oral: gavage

Vehicle:

other: Hydroxypropylmethylcellulose (0.8 %)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 500 mg/mL
- Batch no.: DTR459964

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION: test item was suspended in the vehicle.

CLASS METHOD
- Rationale for the selection of the starting dose: a starting dose of 5000 mg/kg bw has been selected for the following reasons: the study will be used for EU countries implementing the CLP regulation as well as for non-EU countries implementing the GHS regulation. Furthermore, the test item shows a low water solubility. As the bioavailability (and thus solubility) of the test item is a key determinant of toxicity, low toxicity is expected, therefore justifying an initial testing at the limit dose of 5000 mg/kg bw.

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were performed before and immediately, 5, 15, 30 and 60 min, as well as 2, 3, 6 and 24 hours after administration. All surviving animals were observed for a period of 14 days.
Individual body weights were recorded before administration of the test item and thereafter in weekly intervals up to the end of the study and at death.
- Necropsy of survivors performed: yes
At the end of the experiments, all surviving animals were sacrificed, dissected and inspected macroscopically.

Statistics:

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

Preliminary study:

Not applicable

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No premature death was noted.

Clinical signs:

other: Under the present test conditions, animals treated orally with a single dose of 5000 mg test item/kg bw, revealed no signs of toxicity during the 14-day recovery period.

Gross pathology:

Macroscopic examination did not reveal any test item-related findings.

Interpretation of results:

GHS criteria not met

Conclusions:

LD50 (female rats) > 5000 mg/kg bw
According to the Regulation (EC) No 1272/2008 and subsequent adaptations, the substance is not acutely toxic via the oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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:

2021-05-27 to 2021-06-17

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Version / remarks:

2009

Deviations:

yes

Remarks:

please refer to the field `Principles of method if other than guideline´

Principles of method if other than guideline:

- The male and female rats were 6 and 7 weeks old on the exposure day, instead of 8 - 12 weeks;
- The GSD of 3.368 is slightly above the boundaries of 1.5 - 3.
- The exposure was interrupted (for 100 minutes) based on a failure of the compressed air system 10 minutes after start, the animals were immediately removed from the restraining tubes and transferred to their cages. Afterwards, the experiment was continued.

GLP compliance:

yes (incl. QA statement)

Remarks:

signed, 2021-03-31

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

Particle size parameter (equipment: HELOS (H3695) & RODOS/M, R3, Non-GLP determination): x 100 = 30.00 μm (x: particle size; 100: percentage cumulative)

Species:

rat

Strain:

other:

Remarks:

Crl: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age on day of exposure: males: 42 days, females: 49 days
- Weight on day of exposure: males: 237 - 241 g, females: 192 - 203 g
- Fasting period before study: no
- Housing: groups of 3 animals (per sex) in MAKROLON cages (type III plus) with a basal surface of approximately 39 cm (l) x 23 cm (w) x 18 cm (h); bedding material: granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany)
- Diet (ad libitum): ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum): tap water
- Acclimation period: 7 days
- Microbiological status when known: Periodic analysis of the diet, water and bedding material for contaminants based on EPA/USA was conducted by LUFA-ITL

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

1.257 µm

Geometric standard deviation (GSD):

3.368

Remark on MMAD/GSD:

According to OECD Guideline 436, aerosols with a mean aerodynamic mass diameter (MMAD) of 1 to 4 μm with a geometric standard deviation (σg) in the range of 1.5 to 3.0 are recommended to allow exposure of all relevant respiratory tract areas. The MMAD meets the criteria, but the GSD is slightly elevated.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: dynamic inhalation apparatus, RHEMA-LABORTECHNIK, 65719 Hofheim/Taunus, Germany
- Exposure chamber volume: 28.5 L
- Method of holding animals in test chamber: cylindrical exposure chamber, which holds the animals in pyrex tubes at the edge of the chamber in a radial position.
- Source and rate of air (airflow): compressed air (5.0 bar) from a compressor (ALUP Kompressorenfabrik, 73257 Köngen, Germany); inflow / outflow: 900 L/h / 800 L/h
- Method of conditioning air: manometer and an air-flow meter (ROTA Yokogawa GmbH & Co. KG, 79664 Wehr/Baden, Germany) controlled the constant supply of compressed air
- System of generating dust: rotating brush dust generator (RBG 1000, PALAS GmbH Partikel und Lasermesstechnik, Karlsruhe, Germany)
- Method of particle size determination: The particle size was determined by a cascade impactor and by laser diffraction.
- Treatment of exhaust air, pressure in air chamber: at the bottom of the exposure chamber, the air was sucked off at a lower flow rate (800L/h) than it was created by the spray-jet (900L/h) in order to produce a homogenous distribution and a positive pressure in the exposure chamber.
- Temperature, humidity, pressure in air chamber: temperature (22°C ± 3 °C) and humidity (55 % ± 15) were checked once every hour with a climate control monitor (testo 175-HZ data logger).

TEST ATMOSPHERE
- Brief description of analytical method and equipment used:
Analysis of the dust concentration
The aerosol was generated using a rotating brush dust generator. the actual dust concentration in the inhalation chamber was measured gravimetrically with an air sample filter (0.45 μm, Minisart SM 17598) and pump (Membrane Pump MZ 2C,Vacuubrand GmbH + Co. KG, 97877 Wertheim/Main, Germany) controlled by a rotameter (Rota Yokogawa Deutschland GmbH, 40880 Rattingen, Germany). Dust samples were taken once every hour during the exposure close to the animals' noses and air was drawn through the air sample filter at a constant flow of air of 5 L/min for 60 seconds. The filters were weighed before and after sampling (accuracy 0.1 mg). The nominal concentration (total amount of the substance fed into the inhalation equipment divided by volume of air), was calculated.
Particle size distribution (PSD), Mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD):
The dust from the exposure chamber was drawn through a 7 stage cascade impactor (Cascade impactor 6.0 L/min (Article No. 700800-CI-060), TSE Systems GmbH, 61352 Bad Homburg, Germany) twice (70 min and 160 min) during the exposure period, for 5 minutes at a constant flow rate of 5 L/min. The slides were removed and weighed; deltas of slides’ weight were determined.
MMAD was estimated by means of non-linear regression analysis. The 10.6 μm particle size range and the filter (particle size range < 0.55 μm) were not included in the determination of the MMAD in order not to give undue weight to these values. The GSD of the MMAD was calculated from the quotient of the 84.1 % fraction and the 50 % mass fraction, both obtained from the non-linear regression analysis.
A sample of approx. 10 g test material was taken from the exposure chamber and send on 26 May 2021 to My-Tec GmbH, 91325 Adelsdorf, Germany, to determine the median physical particle size with a HELOS (H3695) & RODOS/M, R.

- Samples taken from breathing zone: yes
- Time needed for equilibrium of exposure concentration before animal exposure: 15 min

VEHICLE: no vehicle used

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: a limit dose at a concentration of 5 mg/L was conducted by a request of the Sponsor

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Remarks on duration:

The exposure was interrupted (for 100 min) based on a failure of the compressed air system 10 minutes after start, the animals were immediately removed from the restraining tubes and transferred to their cages. Afterwards, the experiment was continued.

Concentrations:

- Gravimetric (actual) concentration of chrome tungsten titanium buff rutile ± standard deviation [mg/L air]: 5.08 ± 0.03
- Nominal concentration [mg/L air]: 55.56
- Relation of actual to nominal concentration: 0.09

No. of animals per sex per dose:

Limit test:
6 (3 male and 3 female) animals, 2 (1 male and 1 female) reserve animals were additionally employed to the study.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
clinical observations: on the day of exposure, frequently during exposure and twice thereafter; during the observation period (14 days) at least once daily
Body weights: once during the adaptation period, before the exposure, on test days 4, 8, 15 and at time of death.
- Necropsy of survivors performed: yes
- Clinical signs including body weight: changes in the skin and fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern, tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma, indications of respiratory irritation such as dyspnoea.
- Other examinations performed: observations on mortality, isolation or sacrifice of weak or moribund animals; necropsy and macroscopic inspections, lung weights, fixation of organs in 10% (nose (5 levels of the nasal turbinates), i.e. head without brain, eyes, and lower jaw) or 7% buffered formalin (larynx, trachea, lungs (five levels)) for a potential histopathological examination.

Statistics:

not specified

Preliminary study:

not specified

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.08 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

no mortality occured

Clinical signs:

other: None of the animals revealed any signs of toxicity

Body weight:

The body weight gain was in the expected range at the end of the study on test day 15, thus no treatment-related effects were observed.

Gross pathology:

The macroscopic examination did not reveal any changes. No influence on the respiratory tract or the lung weights was noted. Hence, no histopathological examination was performed.

Other findings:

not specified

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the 4-hour inhalation LC50 of Chrome tungsten titanium buff rutile/L air. is >5.08 mg/L air, and hence, the LC50 cut-off value 'unclassified'.
According to the EC Regulation 1272/2008 and subsequent regulations, the test material is not classified for acute inhalation toxicity.

Executive summary:

Three male and three female rats were exposed to an aerosol of chrome tungsten titanium buff rutile at gravimetrically determined concentrations of 5.08 ± 0.03 mg/L air (limit test) for 4 hours by inhalation using a dynamic nose-only exposure chamber.
No signs of toxicity were observed in any of the rats after the 4-hour exposure to the aerosol and the MMAD values (mean 1.257 µm) were within the boundaries of 1 and 4 μm as required by the OECD guideline 436.

Under the present test conditions, the following LC50 value was determined for rats (males and females combined) following a 4-hour inhalation of chrome tungsten titanium buff rutile (gravimetric concentration): LC50 is > 5.08 mg/L air.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5.08

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

One acute oral toxicity study according to OECD guideline 423 has been performed. This study indicates that oral LD50 is >5000 mg/kg bw in rats.

 

For acute inhalation toxicity one animal study has been performed according to OECD TG 436 and which shows no signs of acute toxicity after inhalation exposure to chrome tungsten titanium buff rutile, indicating a LC50 > 5.08 mg/L. No mortalities occured.

 

There are no reliable reports whatsoever on acute dermal toxicity in the public domain. However, the conduct of an acute dermal toxicity study is unjustified as inhalation of the substance is considered as major route of exposure and physicochemical properties of the substance do not suggest a significant rate of absorption through the skin (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).

Justification for classification or non-classification

Acute toxicity oral:

Under the conditions of this study the acute oral median dose (LD50) of the test material was found to be greater than 5000 mg/kg body weight for the male and female animals. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic by the oral route.

 

Specific target organ toxicant (STOT) – single exposure: oral

The classification criteria acc. to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification of 300 mg/kg bw and at the guidance value, oral for a Category 2 classification of 2000 mg/kg bw. No classification required.

 

Acute toxicity inhalation:

No mortality occured at the limit concentration of 5.08 mg/l. Therefore the LC50 is > 5.08 mg/l. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic by the inhalation route.

 

Specific target organ toxicant (STOT) – single exposure: inhalation

The classification criteria acc. to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, inhalation dust/mist/fume are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, inhalation dust/mist/fume for a Category 1 classification of 1.0 mg/L/4h and at the guidance value, inhalation dust/mist/fume for a Category 2 classification of 5.0 mg/L/4h. Therefore, no classification is required.

Finally, any category 3 classification should primarily be based on human data. However, such classification is also not warranted, since observations on respiratory irritation in test animals (rats) were not observed.