Diiron titanium pentaoxide

Endpoint summary

Description of key information

No adverse effects are observed in an oral toxicity study according to OECD TG 401 with the test substance in rats at the limit dose of 5000 mg/kg bw (reference 7.2.1 -1).

Effects have been observed in an acute inhalation toxicity study according to OECD TG 403 using the pigment, which contains 11% of the target substance. However, the effects observed are only due to the massive overload effects (at 14600 mg/m3). No effects are expected at the limit dose recommended by the current OECD guideline (i.e. 2000 mg/m3). The test material is considered not toxic after acute inhalation (reference 7.2.2-1).

No study is available for the acute dermal toxicity. However, due to 1) the composition of this mixed metal oxide (oxides of iron and titanium), 2) the very low solubility in water, and 3) the assumed negligible bioavailability after dermal application, the performance of an acute dermal toxicity study in rats is considered not necessary.

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:

14 February 1990 - 29 March 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1987

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Chbb:THOM

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Thomae, Biberach
- Age at study initiation: 6 to 8 weeks
- Weight at study initiation: mean initial weight 182 (172-196) g
- Fasting period before study: rats did not receive any food from 17 h before up to 4 hours after treatment
- Housing: treated rats were kept separately in Makrolon cages type III
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 - 26
- Humidity (%): 38 - 45
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: aqueous 0.25% hydroxypropyl methylcellulose

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 25 g ad 100 mL
- Amount of vehicle: 20 mL/kg
- Justification for choice of vehicle: solubility

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg

Doses:

Control: 0 mg/kg bw
Treatment group: 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Behavior and general condition of all rats were monitored for 4-6 hours after administration and then checked daily. All rats were weighted before treatment, as well as on days 2,4,6,8,11,13 and 15 of the study.
- Necropsy of survivors performed: yes

Statistics:

The bw data were processed by means of the program TOX 511 A.

Key result

Sex:

male/female

Dose descriptor:

discriminating dose

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed during this study.

Clinical signs:

other: No clinical findings were observed.

Gross pathology:

Gross pathology did not reveal any abnormalities in rats treated the test material.

Other findings:

none

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the discriminating dose in rats after single oral administration was > 5000 mg/kg body weight.

Executive summary:

The acute toxicity potential of the test item was evaluated following single oral administration to male and female Wistar rats at a dose level of 5000 mg/kg bw in aqueous 0.25% hydroxypropyl methylcellulose. No deaths were observed during the study. No clinical signs were observed after application up to the end of the 15 -day observation period. Body weight gain of the treated rats was unaffected. Gross pathology did not reveal any abnormalities.

Based on the results of this study, the maximum non-lethal dose of the test material in rats after single oral administration is >5000 mg/kg bw, and Diiron titanium pentaoxide is considered to have no toxic potential after single administration by the oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

OECD TG 401, GLP

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratory Ltd, Füllinsdorf Switzerland
- Age at delivery:
Males: 8 weeks
Females: 10 weeks
- Weight at delivery:
Males: 180 - 200 g
Females: 180 - 200 g
- Fasting period before study:
- Housing: Groups of 5 in Macrolon type-4 cages
- Diet: Pelleted standard Kliba 343 ad libitum
- Water: Community tab water ad libitum
- Acclimation period:12 or 15 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C +/- 3°C
- Humidity: 30 - 70%
- Air changes: 10 - 15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: according to the method of Sachsse. The animals are confined separately in tubes which are positioned radially around the exposure chamber.
- Exposure chamber volume: 1 liter
- Method of holding animals in test chamber: Macrolon animal restraint tubes
- Exposure airflow rate: 1.3 L/min/animal
- System of generating particulates/aerosols: Piston/brush aerosol generator (RBG 1000, Palas GmbH, Karlsruhe, germany)
- Method of particle size determination: Mercer 7-stage cascade impactor
- Treatment of exhaust air: Rebreathing of exhaled air is precluded
- Temperature, humidity: 21°C, 10 - 15% humidity

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric determination of concentration. The test material was collected on glass fiber filters using a stainless steel filter sampling device. The relative aerosol concentration was monitored using a RAM-1 light scattering type aerosol monitor.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- Particle size distribution (in cumulative %):
Group 2 (4.6 mg/L):
> 4.6 µm 3.0 µm 2.13 µm 1.6 µm 1.06 µm 0.715 µm 0.325 µm < 0.325 µm
100 % 81.5 % 71.7 % 57.9 % 40.9 % 26.3 % 15.5 % 6.8 %

Group 3 (14.9 mg/L):
> 4.6 µm 3.0 µm 2.13 µm 1.6 µm 1.06 µm 0.715 µm 0.325 µm < 0.325 µm
100 % 51.4 % 38.8 % 38.2 % 38.0 % 35.9 % 29.1 % 12.8 %

- MMAD (Mass median aerodynamic diameter):
Group 2 (4.6 mg/L): 1.2 µm
Group 3 (14.9 mg/L): 4.6 µm (slightly exceeds the MMAD-range recommended by the guideline)

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric determination

Duration of exposure:

4 h

Concentrations:

Group 1 (control): 0 mg/L
Group 2: 4.6 mg/L
Group 3: 14.9 mg/L

No. of animals per sex per dose:

5 per sex per group

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Mortality: Once per h during exposure, twice daily until day 15
Body weights: On days 1 (before exposure), 8 and 15
Clinical signs: At least once daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 4.6 - < 14.9 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: local effects on overload on the respiratory tract

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

> 14.9 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Mortality was observed in 60% of the males exposed to the high conc. (14.9 mg/L).
No mortalities have been observed in the control group and the low conc. group (4.6 mg/L)

Clinical signs:

other: During exposure, restlessness in all rats (both sexes) exposed to the high concentration (14.9 mg/L) and in a few animals of both sexes of the lower conc. (4.6 mg/L). At the high conc. (14.9 mg/L): labored respiration in surviviing males, hunched posture

Body weight:

no effects

Gross pathology:

Slightly increased lung weights (not clearly dose-dependent).
In two of the three rats which died sponatneously in the high dose group, the lumen of the trachea was coated with a thick, resistant layer of particles which appeared to be the test material.

Other findings:

High concentration group:
In the 3 males that died spontaneously, irregular brownish particles were noted in bronchi, bronchioles and alveoli. In addition, one of these rats showed slight alveolar hemorrhage and another showed alveolar edema and acute congestion.
In the 7 rats sacrificed on schedule, a slight to moderate alveolar histiocytosis was noted. Most histiocytes (macrophages) contained mainly brownish birefringent particles. Particles were also noted in the bronchi, bronchioles and alveoli of these rats. Granulomas (slight to marked in extent) containing particles were noted in 6 of these rats. Alveolar hemorrhage was noted in 1 of these rats. Perivascular lymphoid cuffing was noted in 5 rats, and chronic alveolitis in all rats sacrificed on schedule.

Low concentration group:
A slight to moderate alveolar histiocytosis was noted in all rats. Most of these histiocytes contained particles. Slight granulomas were noted in 4 rats. Perivascular lymphoid cuffing and chronic alveolitis were noted in 6 rats in 1 of these rats, slight emphysema was also noted.

Control group:
Minimal to slight perivascular lymphoid cuffing and chronic alveolitis were noted in 4 rats.

Interpretation of results:

GHS criteria not met

Conclusions:

The deaths observed in the high concentration group (14.9 mg/L) are assumed to be essential due to local effects of overload on the respiratory tract due to the very high exposure concentration, even in absence of true toxicity of the test material. Deaths may have occured by suffocation produced by overload of inhaled solid particles which exceeded the clearance capacity of the lungs and by partial obstruction of the respiratory airways.

Executive summary:

An acute inhalation toxicity study has been performed. The study was performed according to OECD guideline No. 403 under GLP regulation. Two groups of rats (5 males + 5 females per group) were exposed via the inhalation route (nose only) to the test material at a low or a high concentration (4.6 or 14.9 mg/L, respectively) during a 4h-period. The test material concentrations of both dose groups exceed the limit dose of 2 mg/L as recommended by the guideline. A control group of 5 males and 5 females were exposed under the same conditions to air only.

The MMADs have been determined as 1.2 µm and 4.6 µm for the low and the high concentration, respectively. The MMAD of the high concentration exceeds the specifications of testing guideline of 1 - 4 µm, which is due to the high concentration. Mortality was observed in animals of the high dose group only: 3 of 5 males died spontaneously shortly after start of exposure. Those deaths are assumed to be essential due to local effects of overload on the respiratory tract due to the very high exposure concentration, even in absence of true toxicity of the test material. Deaths may have occured by suffocation produced by overload of inhaled solid particles which exceeded the clearance capacity of the lungs and by partial obstruction of the respiratory airways. No mortality was observed in the females of the high dose group and in the animals of the lower dose group. Therefore, the overall LC50 (male + female rats) was > 4.6 mg/L. Mean body weights were unremarkable and comparable to those of the respective controls. The test material is considered not toxic and the effects observed can be explained by the very high concentrations tested in the course of this study.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Qualifier:

no guideline followed

Principles of method if other than guideline:

Guinea pigs have been exposed for 1 to 2 hours to iron oxide dust and lung functional parameters were determined: Resistance, compliance, tidal volume, frequency, minute volume.

GLP compliance:

no

Test type:

traditional method

Limit test:

yes

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

head only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

>= 0.03 - <= 0.3 µm

Remark on MMAD/GSD:

The geometric mean diameter by count of the iron oxide was 0.076 µm with a geometric standard deviation of 2.0.

Details on inhalation exposure:

Ferric oxide fume was generated by the combustion of iron pentacarbonyl.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

mass concentration: samples were collected on PTFE filters. For aerosol concentrations above 2 mg/m3 amount of aerosol sampled was determined by weighing. At lower concentrations amount of Fe in sample was determined colorimetrically or by AA.

Duration of exposure:

>= 1 - <= 2 h

Remarks on duration:

Measurements were made every five minutes during a half-hour control period and every five minutes during a one-hour or in some instances a two-hour exposure period.

Concentrations:

7 mg/m3 (nominal)

No. of animals per sex per dose:

7 to 9 (sex not determined)

Control animals:

yes

Remarks:

Each animal served as its own control.

Details on study design:

Measurement of the mechanical behavior of the lungs of unanesthetized guinea pigs was used as a means of assessing the respiratory response to the substances tested. The rate of flow of gas in the lungs and airway was measured by electrical differentiation of the volume signal with respect to time.

Dose descriptor:

LC0

Effect level:

> 7 mg/m³ air (nominal)

Exp. duration:

2 h

Interpretation of results:

study cannot be used for classification

Conclusions:

Iron oxide aerosol produced no detectable effect on the respiration of the animals.

Executive summary:

Guinea pigs were exposed head-only for 1 to 2 hours to iron oxide aerosols (7 mg/m3 air nominal) in an plethysmograph and lung functional parameters have been determined. As a result inhalation of iron oxide did not produce any detectable effects. A determination of the LC50 was not possible from this study.

Reference 3

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Qualifier:

no guideline followed

Principles of method if other than guideline:

Guinea pigs have been exposed to different airborne dusts and freshly generated cigarette smoke. The effect was evaluated by counting the number of lung macrophages and leucocytes using a lavage method 24 h after exposure to TiO2 dusts (0.9 mg/m3).

GLP compliance:

no

Test type:

traditional method

Limit test:

yes

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Remark on MMAD/GSD:

< 3 µm = 90 ± 2%
< 7 µm = 99 ± 0.44%

Details on inhalation exposure:

The dust aerosol was generated using a RagPe generator which consists of a fan circulating an airstream with the dust through a circular plastic tube.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The concentration of dust in the chambers was determined by sucking air through Millipore membrane filters which were weighted.

Duration of exposure:

8 h

Concentrations:

0.9 mg/m3

No. of animals per sex per dose:

10 (sex not determined) for test item and 45 for control

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 24 hours
- Frequency of observations and weighing: no data on bodyweight or clinical signs have been reported
- Necropsy of survivors performed: no
- Clinical signs including body weight
- Other examinations performed: BAL measurements performed (macrophasges and leucocytes); number of cells in the preparation was counted under a microscope and a differentiation was made between macrophages and leukocytes. Samples of the washout fluid in certain animals were used to prepare a smear for differential counts using a Shandon-Southern Cytospin (SCA-0030).

Statistics:

Student's t-test

Dose descriptor:

LC50

Remarks on result:

not determinable

Remarks:

number of macrophages slightly increased

Mortality:

No mortality was observed.

Body weight:

no data

Gross pathology:

no data

Interpretation of results:

study cannot be used for classification

Conclusions:

Exposure to TiO2 dusts caused a slight increase in the number of lung macrophages in guinea pigs.

Executive summary:

Guinea pigs have been exposed to different airborne dusts and freshly generated cigarette smoke. The effect was evaluated by counting the number of lung macrophages and leucocytes using a lavage method 24 h after exposure to TiO2 dusts (0.9 mg/m3). TiO2 caused a slight increase in the number of macrophages. No mortality occurred. A determination of the LC50 was not possible from this study.

Reference 4

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For Read-Across Justification please refer to Section 13.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

LC0

Effect level:

> 7 mg/m³ air (analytical)

Exp. duration:

2 h

Reference 5

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For Read-Across Justification please refer to Section 13.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

LC50

Remarks on result:

not determinable

Remarks:

number of macrophages slightly increased

Reference 6

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For Read-Across Justification please refer to Section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 4.6 - < 14.9 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: local effects on overload on the respiratory tract

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 14.9 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

4 600 mg/m³ air

Quality of whole database:

OECD TG 403, GLP

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral

The acute toxicity potential of the test item was evaluated accordimng OECD TG 401 following single oral administration to male and female Wistar rats at a dose level of 5000 mg/kg bw in aqueous 0.25% hydroxypropyl methylcellulose. No deaths were observed during the study. No clinical signs were observed after application up to the end of the 15 -day observation period. Body weight gain of the treated rats was unaffected. Gross pathology did not reveal any abnormalities.

Based on the results of this study, the maximum non-lethal dose of the test material in rats after single oral administration is >5000 mg/kg bw, and Diiron titanium pentaoxide is considered to have no toxic potential after single administration by the oral route.

Acute inhalation

A WoE Approach was used to investigate the acute inhalation toxicity of diiron titanium pentaoxide using data from pigments which contain diiron titanium pentaoxide and data from the oxides titanium dioxide (TiO2) and iron oxide (Fe2O3). There are no data available for diiron titanium pentaoxide.

An acute inhalation toxicity study has been performed with the pigment. The study was performed according to OECD guideline No. 403 under GLP regulation. Two groups of rats (5 males + 5 females per group) were exposed via the inhalation route (nose only) to the test material at a low or a high concentration (4.6 or 14.9 mg/L, respectively) during a 4h-period. The test material concentrations of both dose groups exceed the limit dose of 2 mg/L as recommended by the guideline. A control group of 5 males and 5 females were exposed under the same conditions to air only. The MMADs have been determined as 1.2 µm and 4.6 µm for the low and the high concentration, respectively. The MMAD of the high concentration exceeds the specifications of testing guideline of 1 - 4 µm, which is due to the high concentration. Mortality was observed in animals of the high dose group only: 3 of 5 males died spontaneously shortly after start of exposure. Those deaths are assumed to be essential due to local effects of overload on the respiratory tract due to the very high exposure concentration, even in absence of true toxicity of the test material. Deaths may have occurred by suffocation produced by overload of inhaled solid particles which exceeded the clearance capacity of the lungs and by partial obstruction of the respiratory airways. No mortality was observed in the females of the high dose group and in the animals of the lower dose group. Therefore, the overall LC50 (male + female rats) was > 4.6 mg/L. Mean body weights were unremarkable and comparable to those of the respective controls. The test material is considered not toxic and the effects observed can be explained by the very high concentrations tested in the course of this study.

Furthermore, studies with TiO2 and Fe2O3 are available showing no adverse effects after acute inhalation. However, form these studies no LC50 values could be determined to methodological shortcomings:

Guinea pigs were exposed head-only for 1 to 2 hours to iron oxide aerosols (7 mg/m3 air nominal) in a plethysmograph and lung functional parameters have been determined. As a result inhalation of iron oxide did not produce any detectable effects. In another study Guinea pigs have been exposed to different airborne dusts of TiO2. The effect was evaluated by counting the number of lung macrophages and leucocytes using a lavage method 24 h after exposure to TiO2 dusts (0.9 mg/m3). TiO2 caused a slight increase in the number of macrophages. No mortality occurred.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The available data for acute oral and inhalation toxicity are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on this data, the substance is not classified for acute toxicity under Regulation (EC) No 1272/2008 (CLP), as amended for the twelfth time in Regulation (EU) 2019/521.