Potassium titanium oxide (K1.88-2.13Ti8O16.94-17.07)

Endpoint summary

Description of key information

In a 90 day repeated dose inhalation toxicity study ( OECD 413/OPPTS 870.3465) with rats no adverse effects were observed at 10mg/m3.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 to 25 April 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted under GLP in accordance with an internationally recognised test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD®(SD)IGS BR

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: The mass median aerodynamic equivalent diameter of the aerosols ranged from 2.5 to 2.9 μm.
Geometric standard deviations ranged from 1.3 to 1.6.

Details on inhalation exposure:

Mass median aerodynamic diameter: 2.5 to 2.9 microns

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

During each exposure, the atmospheric concentration of the test substance was determined by gravimetric analysis at approximately hourly intervals in the test chambers.

Duration of treatment / exposure:

Test duration: 90 days

Frequency of treatment:

Duration of exposure per day: 6 hours
Dosing regime: 5 days/week

Remarks:

Doses / Concentrations:
2.0, 10, and 50 mg/m³
Basis:
analytical conc.

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

Four groups of 20 male and 15 female rats each were exposed to aerosols of Terracess TF-S dust at analytically determined concentrations of 2.0, 10, or 50 mg/m³. A similarly comprised control group of rats was simultaneously exposed to air only.

After the conclusion of the exposure phase there were 2 recovery periods of approximately 3 and 15 weeks. At the 3-week recovery, 5 male rats per group were sacrificed and given anatomic pathology examinations; the remaining male and female rats were sacrificed 15 weeks after exposure and also given anatomic pathology examinations.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: during and after exposure + detailed observations once a week

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: not applicable (not a drinking water study)

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to assignment to groups and at the end of the exposure period
- Dose groups that were examined all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10 out of 20 per group

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- Animals fasted: Yes
- How many animals: 10 out of 20 per group
.
URINALYSIS: Yes
- Time schedule for collection of urine: at the end of the exposure period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: near the end of the exposure period
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity

Sacrifice and pathology:

GROSS PATHOLOGY: Digestive System; Cardiovascular System; Musculoskeletal System; Hematopoietic System; Reproductive System; Urinary System;
Endocrine System; Respiratory System; Nervous System;

HISTOPATHOLOGY: Respiratory tract tissues were examined from all rats following the 90-day exposure. These respiratory tract tissues included the nose (4 cross sections), larynx and pharynx (2 cross sections), trachea (1 cross section) and lungs (cross sections of the right apical and caudal lobes; longitudinal section of the left lobe). For those rats selected for lung titanium analysis (5 males/exposure concentration/time point), only the left lung lobe was examined microscopically. In addition to non-polarized light, polarized light was used to examine all respiratory tissue in an effort to maximize identification of the test material within tissue sections.

Other examinations:

skin, and eyes (including optic nerve)

Statistics:

Significance was judged at p < 0.05. Separate analyses were performed on the data collected for each sex.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

not applicable (not a drinking water study)

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

A small increase in lung weight parameters was observed in high-concentration male rats after the 90-day exposure period.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

One high-concentration male was noted to have mottled dark discoloration of the lungs at necropsy while one high-concentration female had diffuse white foci in the lungs, correlating with the microscopic aggregation of particulate-laden macrophages

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Clinical observations:
There were no test-substance related adverse effects on mortality, body weights, clinical signs, neurobehaviour parameters or food consumption during the study. Clinical pathology evaluations showed no effects in haematology, coagulation, serum chemistry, or urine parameters as a result of exposure to Terracess TF-S dust.

Laboratory findings:
At each sacrifice period, sections of the lungs of 4 or 5 male rats per group were collected for titanium content to determine lung deposition and clearance of the test material. Based on this information, the clearance half times for Terracess TF-S were estimated to be in the order of 6 to 9 months for the 50mg/m3 group and 2 to 3 months for the 10 and 2 mg/m3 groups, respectively. These values are in the range of other insoluble, low toxicity dusts
like titanium dioxide.

Organ weight analyses at the end of the exposure period showed a statistically significant increase in lung-to-body weight ratios in the high-level males compared to controls. These differences were no longer present in male rats examined after 3- or 15-week recovery periods.

Effects in organs:
Histologic evaluation showed an exposure-related uptake of aerosol particulates by the resident pulmonary alveolar macrophages within the lung. There was no evidence of increased macrophage numbers, inflammation, or fibrosis. Male rats allowed to recover for 3 and 15 weeks showed migration of pulmonary macrophages into aggregates and gradual clearance of test material. The microscopic findings were consistent with exposure to a non-pathogenic, nuisance dust.

Key result

Dose descriptor:

NOAEL

Effect level:

0.01 mg/L air

Basis for effect level:

other: exposure duration: 6 hours/day

Key result

Critical effects observed:

not specified

Conclusions:

Under the conditions of the study, the no-effect level (NOAEL) for rats exposed to the test substance for approximately 90-days was 10 mg/cubic metre based on reversible lung weight effects in male rats at the highest exposure level.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

10 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 to 25 April 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted under GLP in accordance with an internationally recognised test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD®(SD)IGS BR

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: The mass median aerodynamic equivalent diameter of the aerosols ranged from 2.5 to 2.9 μm.
Geometric standard deviations ranged from 1.3 to 1.6.

Details on inhalation exposure:

Mass median aerodynamic diameter: 2.5 to 2.9 microns

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

During each exposure, the atmospheric concentration of the test substance was determined by gravimetric analysis at approximately hourly intervals in the test chambers.

Duration of treatment / exposure:

Test duration: 90 days

Frequency of treatment:

Duration of exposure per day: 6 hours
Dosing regime: 5 days/week

Remarks:

Doses / Concentrations:
2.0, 10, and 50 mg/m³
Basis:
analytical conc.

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

Four groups of 20 male and 15 female rats each were exposed to aerosols of Terracess TF-S dust at analytically determined concentrations of 2.0, 10, or 50 mg/m³. A similarly comprised control group of rats was simultaneously exposed to air only.

After the conclusion of the exposure phase there were 2 recovery periods of approximately 3 and 15 weeks. At the 3-week recovery, 5 male rats per group were sacrificed and given anatomic pathology examinations; the remaining male and female rats were sacrificed 15 weeks after exposure and also given anatomic pathology examinations.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: during and after exposure + detailed observations once a week

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: not applicable (not a drinking water study)

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to assignment to groups and at the end of the exposure period
- Dose groups that were examined all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10 out of 20 per group

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- Animals fasted: Yes
- How many animals: 10 out of 20 per group
.
URINALYSIS: Yes
- Time schedule for collection of urine: at the end of the exposure period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: near the end of the exposure period
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity

Sacrifice and pathology:

GROSS PATHOLOGY: Digestive System; Cardiovascular System; Musculoskeletal System; Hematopoietic System; Reproductive System; Urinary System;
Endocrine System; Respiratory System; Nervous System;

HISTOPATHOLOGY: Respiratory tract tissues were examined from all rats following the 90-day exposure. These respiratory tract tissues included the nose (4 cross sections), larynx and pharynx (2 cross sections), trachea (1 cross section) and lungs (cross sections of the right apical and caudal lobes; longitudinal section of the left lobe). For those rats selected for lung titanium analysis (5 males/exposure concentration/time point), only the left lung lobe was examined microscopically. In addition to non-polarized light, polarized light was used to examine all respiratory tissue in an effort to maximize identification of the test material within tissue sections.

Other examinations:

skin, and eyes (including optic nerve)

Statistics:

Significance was judged at p < 0.05. Separate analyses were performed on the data collected for each sex.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

not applicable (not a drinking water study)

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

A small increase in lung weight parameters was observed in high-concentration male rats after the 90-day exposure period.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

One high-concentration male was noted to have mottled dark discoloration of the lungs at necropsy while one high-concentration female had diffuse white foci in the lungs, correlating with the microscopic aggregation of particulate-laden macrophages

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Clinical observations:
There were no test-substance related adverse effects on mortality, body weights, clinical signs, neurobehaviour parameters or food consumption during the study. Clinical pathology evaluations showed no effects in haematology, coagulation, serum chemistry, or urine parameters as a result of exposure to Terracess TF-S dust.

Laboratory findings:
At each sacrifice period, sections of the lungs of 4 or 5 male rats per group were collected for titanium content to determine lung deposition and clearance of the test material. Based on this information, the clearance half times for Terracess TF-S were estimated to be in the order of 6 to 9 months for the 50mg/m3 group and 2 to 3 months for the 10 and 2 mg/m3 groups, respectively. These values are in the range of other insoluble, low toxicity dusts
like titanium dioxide.

Organ weight analyses at the end of the exposure period showed a statistically significant increase in lung-to-body weight ratios in the high-level males compared to controls. These differences were no longer present in male rats examined after 3- or 15-week recovery periods.

Effects in organs:
Histologic evaluation showed an exposure-related uptake of aerosol particulates by the resident pulmonary alveolar macrophages within the lung. There was no evidence of increased macrophage numbers, inflammation, or fibrosis. Male rats allowed to recover for 3 and 15 weeks showed migration of pulmonary macrophages into aggregates and gradual clearance of test material. The microscopic findings were consistent with exposure to a non-pathogenic, nuisance dust.

Key result

Dose descriptor:

NOAEL

Effect level:

0.01 mg/L air

Basis for effect level:

other: exposure duration: 6 hours/day

Key result

Critical effects observed:

not specified

Conclusions:

Under the conditions of the study, the no-effect level (NOAEL) for rats exposed to the test substance for approximately 90-days was 10 mg/cubic metre based on reversible lung weight effects in male rats at the highest exposure level.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

10 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In a subchronic 90 -day repeat dose study conducted in accordance with OECD 413 and OPPTS 270.2600 guidelines four groups 20 male and female rats were exposed to aerosol concentrations of 2.0, 10, or 50 mg/m3 .

There were no test-substance related systemic adverse effects with no mortality, and no significant changes to body weight, clinical signs, neurobehavior parameters or food consumption during the study. Clinical pathology evaluations showed no effects in urine, hematology, coagulation, or blood chemistry parameters as a result of exposure to Terracess TF-S dust.

Local effects were observed with a statistically significant increase in lung-to-body weight ratios in the high-level males compared to controls but these effects were reversible an no longer present in male rats examined after 3 - or 15 -weeks during the recovery period.

Lung analysis for titanium content was used to determine lung deposition and clearance of the test material and showed that the clearance ½ times for Terracess TF-S to be in the order of 6 to 9 months for the 50 mg/m³ group and 2 to 3 months for the 10 and 2 mg/m³ groups, respectively. These values are in the range of other insoluble, low toxicity dusts like titanium dioxide. . Histologic evaluation showed an exposure-related uptake of aerosol particulates by the resident pulmonary alveolar macrophages within the lung. There was no evidence of increased macrophage numbers, inflammation, or fibrosis. The male rats allowed to recover for 3 and 15 weeks showed migration of pulmonary macrophages into aggregates and gradual clearance of test material. The microscopic findings were consistent with exposure to a non-pathogenic, nuisance dust.

Under the conditions of this study, the no-effect level (NOEL)a for rats exposed to Terracess TF-S for approximately 90 days was 10 mg/m³ based on reversible lung weight effects in male rats at the highest exposure level.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

One valid and available subchronic study

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

One valid and available subchronic study

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

Although Terracess TF is shown to have adverse effects, these are reversible and due to physical accumulation rather than any toxic effect. Based on the available data Terracess TF does not have to be classified for repeated dose toxicity according to CLP Regulation EC (No.) 1272/2008.