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Toxicological information

Carcinogenicity

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Description of key information

The key information used to judged the quality and the appropriateness of the information gathered were:

1. route of exposure

2. experimented substances versus Potassium hexatitanate.

3. relative quantity of whisker in the sample

1. The most representative route of exposure was judged to be inhalation.

2. the relevance of the experimented substances for the substance object of the registration dossier (Potassium hexatitanate): the substances were judged as quite similar so, the data available for the other substances could be switched to Potassium hexatitante in order to fill the gap of information.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: inhalation
Type of information:
other: data from analogue substance
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
The potassium titanates represent a "family" of inorganic substances made by titanium (Ti), oxygen (O) and potassium (K).
The members of this family of substances differ each other in relation to the ratio stoichiometric of the three structural elements within the unit.
The substances are identified and listed below:
- Potassium titanate CAS No. 12030-97-6 (K2TiO3)
- Potassium titanate CAS No. 12056-46-1 (K2Ti2O5)
- Potassium titanate CAS No. 12056-49-4 (K2Ti4O9)
- Potassium titanate CAS No. 12056-51-8 (K2Ti6O13)
- Potassium titanate CAS No. 12056-53-0 (KTi4O8)
- Potassium titanate CAS No. 59766-31-3 (K2Ti8O17)

One of the critical aspects that distinguishes the different substances is the fibrousness of echa specific substances.
These substances are composed by 2 parts: an "amorphous" and a fibrous, in different ratio.

Overall, available data obtained from animal tests, which were performed by inhalation exposure or intratracheal/intraperitoneal administration of the substance, do not show carcinogenic activity. However, the substance may exist both in fibrous and in non-fibrous state.
According to carcinogenic effects recognized for other fibrous materials, the classification in category 2 appears to be justified only if the potassium hexatitanate fibers content is >= 1%.
In the Legal Entity Composition, le fiber content is < 1% and it was classified as not carcinogenic.
Qualifier:
no guideline followed
GLP compliance:
not specified
Specific details on test material used for the study:
The test material was potassium octatitanate (Fybex, (R) du Pont) fibers that revealed needle-like fine rods
Species:
guinea pig
Strain:
not specified
Details on species / strain selection:
albino
Sex:
male
Details on test animals or test system and environmental conditions:
no data
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Mass median aerodynamic diameter (MMAD):
ca. 0.2 µm
Details on exposure:
Five-cubic-meter exposure chambers were used for the dust exposure.
The number of Fybex fibers (longer than 5 micron in length) per liter of air was 2.9 x10^6.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
1) 3 months
Frequency of treatment:
6 hours per day, 5 daysper week
Post exposure period:
After 3 months of exposure the animals were placed in the recovery rooms and sacrificed 15-24 months later in both experiment (the first and the second).
Dose / conc.:
0.079 other: mg/l
Remarks:
Experiment I - gravimetric exposure concentration
Dose / conc.:
0.039 mg/L air
Remarks:
Experiment II - gravimetri exposure concentration
Dose / conc.:
0.082 mg/L air
Remarks:
Experiment II - gravimetric exposure concentration
Dose / conc.:
0.37 mg/L air
Remarks:
Experiment II -gravimetric exposure concentration
No. of animals per sex per dose:
The number of animals was 11 guinea pigs, for the first experiment.
In the second, guinea pigs were divided into 3 groups and were exposed to Fybex fibers at 3 different exposure concentrations.
The number of animals was 17 at 2.9 x 106/l;
18 guinea pigs at 13.5 x 106/l;
16 guinea pigs at 41.8 x 106/l;
and 17guinea pigs as a control group, exposed to air served as a control.
Control animals:
yes
Positive control:
no data
Observations and examinations performed and frequency:
All organs and tissues from each animal were fixed.
Statistics:
no data
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Description (incidence and severity):
no data
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Numerous dust cells were transported to the tracheobronchial and mediastinal lymph nodes, where they entered into the lymphatic or blood circulation.
There was massive direct migration of the dust cells from the lymph nodes to the mediastinal adipose tissue.
The dust cells in the lungs migrated directly to the pulmonary pleura and produced initially marked hyperplasia of submesothelial cells, and, later, mesothelial
hyperplasia or mesothelioma, in which numerous dust particles were embedded in the centrai collagenized core.
Some dust cells migrated further, reaching the epicardium and parietal pleura through pleural adhesions, and produced fibrosis or mesothelial hyperplasia.
Fibrogenicity or carcinogenicity of asbestos and other fibrous dust particles were related to fiber length an d diameter, Short fibers (<5 micron) were not only devoid of fibrogenicity but also of carcinogenicity.
Other effects:
not examined
Details on results:
experimental animals were exposed to fibrous dust particles by the natura! exposure route and revealed migrating fibers in both blood and lymphatic vessels.
In Fybex-exposed animals, migrating fibers were found often in the glomerular tufts, renal tubules, and interstitium of the kidneys.
Inorganic fibers produced similar pulmonary responses to asbestos fibers in experimental animals.
Relevance of carcinogenic effects / potential:
The highest probability of a pleural tumor was obtained by fibrous dust particles less than 0.25 micron diameter and greater than 81micron in length, whereas no tumor was induced by short and coarse fibers (>3 micron in diameter).
Considering the size-related fibrogenicity or carcinogenicity of fibrous dust particles, there is some doubt about the human health hazard posed by submicroscopic particles.
Dose descriptor:
other: lenght
Effect level:
< 5 other: micron
Based on:
test mat.
Sex:
not specified
Basis for effect level:
histopathology: neoplastic
Remarks on result:
other: short fibers (<5 micron) induced mostly macrophage reaction
Dose descriptor:
other: lenght
Effect level:
> 10 other: micron
Based on:
test mat.
Sex:
not specified
Basis for effect level:
histopathology: neoplastic
Remarks on result:
other: longer fibers (>10 micron) produced. giant cel formation.in the lungs
Conclusions:
A few pulmonary monary tumors developed in animals exposed to Fybex, but their numbers were too small to draw any conclusions on the carcinogenicity.
Considering the relatively rare incidence of mesothelioma in control, the possibility that mesothelioma in exposed animals is related to the Fybex exposure cannot
be ruled out.
Dust-laden macrophages or giant cells were occasionally observed in the liver, but other organs showed a few dust-laden macrophages or extracellular
fibers without any tissue reactions. In the gastrointestinal tract, a few dust cells were occasionallyfound in the mucosa or submucosa but not the muscle
layers. These microscopic findings cast some doubt on the hypothesis that ingested fibrous particles from lung clearance mechanisms following inhalation exposure can penetrate the gastrointestinal tract and induce either cancer or peritoneal mesothelioma.
Executive summary:

Rats, were exposed by inhalation to different concentrations of potassium octatitanate fibers. Following 3 months of exposure, the animals were sacrificed between the 15th and 24th month. The exposed animals showed dose-related dust deposition and pulmonary fibrosis mainly in the respiratory bronchiolar region. Most short fibers ( vessels. N umerous dust cells w ere transported from the lung to the tracheobronchial and mediastinal lymph nodes where some dust cells penetrated into the blood or lymphatic circulation. Massive direct celi migration of the mediastinal adipose tissue from the lymph nodes occurred occasionally. Dust-laden giant cells were found only occasionally in the liver, and there was widespread migration of the fibers into other vi tal organs and tissues without any significant responses

Endpoint:
carcinogenicity: inhalation
Type of information:
other: data from analogue substance
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
The potassium titanates represent a "family" of inorganic substances made by titanium (Ti), oxygen (O) and potassium (K).
The members of this family of substances differ each other in relation to the ratio stoichiometric of the three structural elements within the unit.
The substances are identified and listed below:
- Potassium titanate CAS No. 12030-97-6 (K2TiO3)
- Potassium titanate CAS No. 12056-46-1 (K2Ti2O5)
- Potassium titanate CAS No. 12056-49-4 (K2Ti4O9)
- Potassium titanate CAS No. 12056-51-8 (K2Ti6O13)
- Potassium titanate CAS No. 12056-53-0 (KTi4O8)
- Potassium titanate CAS No. 59766-31-3 (K2Ti8O17)

One of the critical aspects that distinguishes the different substances is the fibrousness of echa specific substances.
These substances are composed by 2 parts: an "amorphous" and a fibrous, in different ratio.

Overall, available data obtained from animal tests, which were performed by inhalation exposure or intratracheal/intraperitoneal administration of the substance, do not show carcinogenic activity. However, the substance may exist both in fibrous and in non-fibrous state.
According to carcinogenic effects recognized for other fibrous materials, the classification in category 2 appears to be justified only if the potassium hexatitanate fibers content is >= 1%.
In the Legal Entity Composition, le fiber content is < 1% and it was classified as not carcinogenic.
Qualifier:
no guideline followed
GLP compliance:
not specified
Specific details on test material used for the study:
The test material was potassium octatitanate (Fybex, (R) du Pont) fibers that revealed needle-like fine rods
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
no data
Sex:
male
Details on test animals or test system and environmental conditions:
no data
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Mass median aerodynamic diameter (MMAD):
ca. 0.2 µm
Details on exposure:
Five-cubic-meter exposure chambers were used for the dust exposure.
The number of Fybex fibers (longer than 5 micron in length) per liter of air was 2.9 x10^6.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
1) 3 months
Frequency of treatment:
6 hours per day, 5 daysper week
Post exposure period:
After 3 months of exposure the animals were placed in the recovery rooms and sacrificed 15-24 months later in both experiment (the first and the second).
Dose / conc.:
0.079 other: mg/l
Remarks:
Experiment I - gravimetric concentration
Dose / conc.:
0.039 mg/L air
Remarks:
Experimenti II - gravimetri exposure concentration
Dose / conc.:
0.082 mg/L air
Remarks:
Experiment III - gravimetric exposure concentration
Dose / conc.:
0.37 mg/L air
Remarks:
Experiment II - gravimetric exposure concentration
No. of animals per sex per dose:
The number of animals was 12 hamster, for the first experiment.
In the second, hamsters were divided into 3 groups and were exposed to Fybex fibers at 3 different exposure concentrations.
The number of animals was 18 at 2.9 x 10^6/l;
13 hamsters at 13.5 x 10^6/l;
16 hamsters at 41.8 x 106/l;
and 10 hamsters as a control group, exposed to air served as a control.
Control animals:
yes
Positive control:
no data
Observations and examinations performed and frequency:
All organs and tissues from each animai were fixed.
Sacrifice and pathology:
no data
Other examinations:
no data
Statistics:
no data
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Description (incidence and severity):
no data
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Numerous dust cells were transported to the tracheobronchial and mediastinal lymph nodes, where they entered into the lymphatic or blood circulation.
There was massive direct migration of the dust cells from the lymph nodes to the mediastinal adipose tissue.
The dust cells in the lungs migrated directly to the pulmonary pleura and produced initially marked hyperplasia of submesothelial cells, and, later, mesothelial hyperplasia or mesothelioma, in which numerous dust particles were embedded in the centrai collagenized core.
Some dust cells migrated further, reaching the epicardium and parietal pleura through pleural adhesions, and produced fibrosis or mesothelial hyperplasia.
Fibrogenicity or carcinogenicity of asbestos and other fibrous dust particles were related to fiber length an d diameter, Short fibers (<5 micron) were not only devoid of fibrogenicity but also of carcinogenicity.
Other effects:
not examined
Details on results:
experimental animals were exposed to fibrous dust particles by the natura! exposure route and revealed migrating fibers in both blood and lymphatic vessels.
In Fybex-exposed animals, migrating fibers were found often in the glomerular tufts, renal tubules, and interstitium of the kidneys.
Inorganic fibers produced similar pulmonary responses to asbestos fibers in experimental animals.
Relevance of carcinogenic effects / potential:
The highest probability of a pleural tumor was obtained by fibrous dust particles less than 0.25 micron diameter and greater than 81micron in length, whereas no tumor was induced by short and coarse fibers (>3 micron in diameter).
Considering the size-related fibrogenicity or carcinogenicity of fibrous dust particles, there is some doubt about the human health hazard posed by submicroscopic particles.
Dose descriptor:
other: lenght
Effect level:
< 5 other: micron
Based on:
test mat.
Sex:
not specified
Basis for effect level:
histopathology: neoplastic
Remarks on result:
other: short fibers (<5 micron) induced mostly macrophage reaction
Dose descriptor:
other: lenght
Effect level:
> 10 other: micron
Based on:
test mat.
Sex:
not specified
Basis for effect level:
histopathology: neoplastic
Remarks on result:
other: longer fibers (>10 micron) produced. giant cel formation.in the lungs
Conclusions:
A few pulmonary monary tumors developed in animals exposed to Fybex, but their numbers were too small to draw any conclusions on the carcinogenicity.
Considering the relatively rare incidence of mesothelioma in control, the possibility that mesothelioma in exposed animals is related to the Fybex exposure cannot
be ruled out.
Dust-laden macrophages or giant cells were occasionally observed in the liver, but other organs showed a few dust-laden macrophages or extracellular
fibers without any tissue reactions. In the gastrointestinal tract, a few dust cells were occasionallyfound in the mucosa or submucosa but not the muscle
layers. These microscopic findings cast some doubt on the hypothesis that ingested fibrous particles from lung clearance mechanisms following inhalation exposure can penetrate the gastrointestinal tract and induce either cancer or peritoneal mesothelioma.
Executive summary:

Rats, were exposed by inhalation to different concentrations of potassium octatitanate fibers. Following 3 months of exposure, the animals were sacrificed between the 15th and 24th month. The exposed animals showed dose-related dust deposition and pulmonary fibrosis mainly in the respiratory bronchiolar region. Most short fibers ( vessels. N umerous dust cells w ere transported from the lung to the tracheobronchial and mediastinal lymph nodes where some dust cells penetrated into the blood or lymphatic circulation. Massive direct celi migration of the mediastinal adipose tissue from the lymph nodes occurred occasionally. Dust-laden giant cells were found only occasionally in the liver, and there was widespread migration of the fibers into other vi tal organs and tissues without any significant responses

Endpoint:
carcinogenicity: inhalation
Type of information:
other: data from analogue substance
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
The potassium titanates represent a "family" of inorganic substances made by titanium (Ti), oxygen (O) and potassium (K).
The members of this family of substances differ each other in relation to the ratio stoichiometric of the three structural elements within the unit.
The substances are identified and listed below:
- Potassium titanate CAS No. 12030-97-6 (K2TiO3)
- Potassium titanate CAS No. 12056-46-1 (K2Ti2O5)
- Potassium titanate CAS No. 12056-49-4 (K2Ti4O9)
- Potassium titanate CAS No. 12056-51-8 (K2Ti6O13)
- Potassium titanate CAS No. 12056-53-0 (KTi4O8)
- Potassium titanate CAS No. 59766-31-3 (K2Ti8O17)

One of the critical aspects that distinguishes the different substances is the fibrousness of echa specific substances.
These substances are composed by 2 parts: an "amorphous" and a fibrous, in different ratio.

Overall, available data obtained from animal tests, which were performed by inhalation exposure or intratracheal/intraperitoneal administration of the substance, do not show carcinogenic activity. However, the substance may exist both in fibrous and in non-fibrous state.
According to carcinogenic effects recognized for other fibrous materials, the classification in category 2 appears to be justified only if the potassium hexatitanate fibers content is >= 1%.
In the Legal Entity Composition, le fiber content is < 1% and it was classified as not carcinogenic.
Qualifier:
no guideline followed
GLP compliance:
not specified
Specific details on test material used for the study:
The test material was potassium octatitanate (Fybex, (R) du Pont) fibers that revealed needle-like fine rods
Species:
hamster, Syrian
Strain:
not specified
Remarks:
Charles River-CD Sprague-Dawley-derived
Details on species / strain selection:
no data
Sex:
male
Details on test animals or test system and environmental conditions:
no data
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Mass median aerodynamic diameter (MMAD):
ca. 0.2 µm
Details on exposure:
Five-cubic-meter exposure chambers were used for the dust exposure.
The number of Fybex fibers (longer than 5 micron in length) per liter of air was 2.9 x10^6.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
1) 3 months
Frequency of treatment:
6 hours per day, 5 daysper week
Post exposure period:
After 3 months of exposure the animals were placed in the recovery rooms and sacrificed 15-24 months later in both experiment (the first and the second).
Dose / conc.:
0.079 other: mg/l
Remarks:
Experiment I - gravimetric concentration
Dose / conc.:
0.039 mg/L air
Remarks:
Experimenti II - gravimetri exposure concentration
Dose / conc.:
0.082 mg/L air
Remarks:
Experiment III - gravimetric exposure concentration
Dose / conc.:
0.37 mg/L air
Remarks:
Experiment II - gravimetric exposure concentration
No. of animals per sex per dose:
The number of animals was 21 rats, for the first experiment.

In the second, rats were divided into 3 groups and were exposed to Fybex fibers at 3 different exposure concentrations.
The number of animals was 21 at 2.9 x 106/l;
25 rats at 13.5 x 106/l;
19 rats at 41.8 x 106/l;
and 23 rats as a control group, exposed to air served as a control.
Control animals:
yes
Positive control:
no data
Observations and examinations performed and frequency:
All organs and tissues from each animai were fixed.
Sacrifice and pathology:
no data
Other examinations:
no data
Statistics:
no data
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Description (incidence and severity):
no data
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Numerous dust cells were transported to the tracheobronchial and mediastinal lymph nodes, where they entered into the lymphatic or blood circulation.
There was massive direct migration of the dust cells from the lymph nodes to the mediastinal adipose tissue.
The dust cells in the lungs migrated directly to the pulmonary pleura and produced initially marked hyperplasia of submesothelial cells, and, later, mesothelial hyperplasia or mesothelioma, in which numerous dust particles were embedded in the centrai collagenized core.
Some dust cells migrated further, reaching the epicardium and parietal pleura through pleural adhesions, and produced fibrosis or mesothelial hyperplasia.
Fibrogenicity or carcinogenicity of asbestos and other fibrous dust particles were related to fiber length an d diameter, Short fibers (<5 micron) were not only devoid of fibrogenicity but also of carcinogenicity.
Other effects:
not examined
Details on results:
experimental animals were exposed to fibrous dust particles by the natura! exposure route and revealed migrating fibers in both blood and lymphatic vessels.
In Fybex-exposed animals, migrating fibers were found often in the glomerular tufts, renal tubules, and interstitium of the kidneys.
Inorganic fibers produced similar pulmonary responses to asbestos fibers in experimental animals.
Relevance of carcinogenic effects / potential:
The highest probability of a pleural tumor was obtained by fibrous dust particles less than 0.25 micron diameter and greater than 81micron in length, whereas no tumor was induced by short and coarse fibers (>3 micron in diameter).
Considering the size-related fibrogenicity or carcinogenicity of fibrous dust particles, there is some doubt about the human health hazard posed by submicroscopic particles.
Dose descriptor:
other: lenght
Effect level:
< 5 other: micron
Based on:
test mat.
Sex:
not specified
Basis for effect level:
histopathology: neoplastic
Remarks on result:
other: short fibers (<5 micron) induced mostly macrophage reaction
Dose descriptor:
other: lenght
Effect level:
> 10 other: micron
Based on:
test mat.
Sex:
not specified
Basis for effect level:
histopathology: neoplastic
Remarks on result:
other: longer fibers (>10 micron) produced. giant cel formation.in the lungs
Conclusions:
A few pulmonary monary tumors developed in animals exposed to Fybex, but their numbers were too small to draw any conclusions on the carcinogenicity.
Considering the relatively rare incidence of mesothelioma in control, the possibility that mesothelioma in exposed animals is related to the Fybex exposure cannot
be ruled out.
Dust-laden macrophages or giant cells were occasionally observed in the liver, but other organs showed a few dust-laden macrophages or extracellular
fibers without any tissue reactions. In the gastrointestinal tract, a few dust cells were occasionallyfound in the mucosa or submucosa but not the muscle
layers. These microscopic findings cast some doubt on the hypothesis that ingested fibrous particles from lung clearance mechanisms following inhalation exposure can penetrate the gastrointestinal tract and induce either cancer or peritoneal mesothelioma.
Executive summary:

Rats, were exposed by inhalation to different concentrations of potassium octatitanate fibers. Following 3 months of exposure, the animals were sacrificed between the 15th and 24th month. The exposed animals showed dose-related dust deposition and pulmonary fibrosis mainly in the respiratory bronchiolar region. Most short fibers ( vessels. N umerous dust cells w ere transported from the lung to the tracheobronchial and mediastinal lymph nodes where some dust cells penetrated into the blood or lymphatic circulation. Massive direct celi migration of the mediastinal adipose tissue from the lymph nodes occurred occasionally. Dust-laden giant cells were found only occasionally in the liver, and there was widespread migration of the fibers into other vi tal organs and tissues without any significant responses

Endpoint:
carcinogenicity, other
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
GLP compliance:
not specified
Species:
other: J774 cells
Strain:
other: not relevant
Details on species / strain selection:
not relevant
Sex:
not specified
Endpoint:
carcinogenicity: inhalation
Type of information:
other: data from analogue substance
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
The potassium titanates represent a "family" of inorganic substances made by titanium (Ti), oxygen (O) and potassium (K).
The members of this family of substances differ each other in relation to the ratio stoichiometric of the three structural elements within the unit.
The substances are identified and listed below:
- Potassium titanate CAS No. 12030-97-6 (K2TiO3)
- Potassium titanate CAS No. 12056-46-1 (K2Ti2O5)
- Potassium titanate CAS No. 12056-49-4 (K2Ti4O9)
- Potassium titanate CAS No. 12056-51-8 (K2Ti6O13)
- Potassium titanate CAS No. 12056-53-0 (KTi4O8)
- Potassium titanate CAS No. 59766-31-3 (K2Ti8O17)

One of the critical aspects that distinguishes the different substances is the fibrousness of echa specific substances.
These substances are composed by 2 parts: an "amorphous" and a fibrous, in different ratio.

Overall, available data obtained from animal tests, which were performed by inhalation exposure or intratracheal/intraperitoneal administration of the substance, do not show carcinogenic activity. However, the substance may exist both in fibrous and in non-fibrous state.
According to carcinogenic effects recognized for other fibrous materials, the classification in category 2 appears to be justified only if the potassium hexatitanate fibers content is >= 1%.
In the Legal Entity Composition, le fiber content is < 1% and it was classified as not carcinogenic.
Qualifier:
no guideline followed
GLP compliance:
not specified
Specific details on test material used for the study:
crystalline whisker (coded as PT1)
Species:
rat
Strain:
Wistar
Details on species / strain selection:
5 wk old at the start of exposure
Sex:
male
Details on test animals or test system and environmental conditions:
no data
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Mass median aerodynamic diameter (MMAD):
24 µm
Remarks on MMAD:
PT1: 1.7 (24) microm
Details on exposure:
The length and diameter of the PT1 in the exposure chamber were measured with a scanning electron microscope (S-900, Hitachi, Japan). The geometrie mean length (GSD) and geometric mean diameter (GSD) were 3.4 (2.7) microm and 0.44 (1.4) microm respectively. The
mass median aerodynamic diameter (MMAD) of the PT1 1.7 (24) microm was determined using an Andersen cascade impactor (model AN-200, Sibata Sci Tech Ltd, Japan).
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
1 y
Frequency of treatment:
6h/day, 5 days/week.
Dose / conc.:
2.2 other: mg/m3
Remarks:
2.2 ± 0.7 mg/rnl (111 ± 34 fiber/m/); This concentration is almost equal to the lega lly designated occupational exposure limits of PT1 (2.9 mg/m3) in Japan.
No. of animals per sex per dose:
Fifty-nine male Wistar rats (5 wk old at the start of exposure) were randomly divided into exposure and groups.
Control animals:
yes
Details on study design:
In order to confirm the pulmonary effects of inhaled PT1 , we carried out a long-term, low-exposure inhalation study in rats.
Positive control:
no data
Observations and examinations performed and frequency:
Measurement of Lung Burden of PT1 Whiskers in Lungs
Histopathological Examination
Overall Survival of Rats
Growth Curve of Rats
Sacrifice and pathology:
Five rats from each group were randomly selected and sacrifi ced at 3 days and 6 mo after the end of 1-yr inhalation exposure; the remaining rats were sacri ficed at 12 mo.
Other examinations:
no data
Statistics:
Overall survival of rats: Statistical analys is was carried out using a Statview software package (Abacus Concepts, Berkeley, CA).
Body weight: For the statistical analys is, an unpaired t-test was used to assess the differences in the mean value of body and wet lung weight of the rats
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not specified
Description (incidence):
Nine exposed rats died during the postexposure period. One control rat died during the exposure period, while eight contro! rats died during the
postexposure period.
The overall survival rates were calculated by the Kaplan- Meier method and showed no significant differences in the overall survival curves between the exposure an d the contro l rats (p= . 98)
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There was no significant difference in body weight between the exposure and the contro! rats during the exposure and postexposure periods. There was also no significant difference in wet lung weight between the exposed and the control rats.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Description (incidence and severity):
The histopathological changes of accessory lobes observed in the exposed and control rats: almost ali the rats that died due to fibroma showed extrapulmonary lesions during the observation period.
As for the fibrogenicity of PT1 , thickening of the alveolar walls was observed only around the macrophages that engulfed the PT1. increase of reticulin fibers in the thickened alveolar walls observed only around the dust cells.
Thickening of pleura was observed in both the exposure and the control rats.
These mild fibroti c changes (not massive fibrotic change) were observed in ali the exposed rats. Bronchiolization was observed in all the exposed rats. Most of this change was observed at the level of bronchoalveolar junction
Histopathological findings: neoplastic:
not specified
Description (incidence and severity):
As to the tumorous lesions in accessory lobes, there were no malignant tumors in either the exposed or the contro! rats. However, 2 cases of ademona among 5 rats at 6 mo and 1 case of adenoma and 1 squamous metaplasia among 11 rats at 12 months after the end of 1-yr inhalation
were found in exposed rats.
Other effects:
not specified
Description (incidence and severity):
Lung burden: The lung burden was 2.4 ± 0.7 mg at 3 days after 1-yr inhalation exposure.
The deposition fraction of PT1 was 7.2% at 3 days after 1-yr exposure.
Relevance of carcinogenic effects / potential:
The findings suggest that PT1 possesses a mild fibrogenetic potential.
Some cases of carcinogenic lesions were observed in exposed rats, while they were not observed in the rats exposed to other MMFs
in our previous studies or control rats in this study. These results suggest that PT1 could possess mild carcinogenic potential.
Dose descriptor:
dose level:
Effect level:
2.2 other: mg/m3
Based on:
test mat.
Sex:
male
Basis for effect level:
other: pulmonary effects and clearence
Remarks on result:
other:
Remarks:
NOAEL not determinable

PT1 is a suitable whisker for studying how fibrous material with small solubility cleared from lungs. Dust cells remained in lungs for a long period after the inhalation exposure. lt is considered that the clearance of short whiskers in dust cells might be disturbed. Additionally, PT1 whiskers longer than macrophages in length cou ld not be engulfed by macrophages. Those long fibers would exist in lungs fora long period because of the small dissolution rate of PT1 to the body fluid (Shutou et al., 1992).

Many macrophages that engulfed short whiskers (dust cells) were found in the lungs at 12 mo after the end of inhalation. lt is considered that the ability of dust cells to migrate to mucoci liary transportation system or lymphatic system is impaired. Additionally, whiskers longer than macrophages would stay in alveolar walls without dissolution to body fluid. lt is considered that some portion of short whiskers would be rapidly eliminated through macrophage mediated clearance after inhalation exposure. The clearance of short whiskers in the dust cell s and long whiskers inalveolar walls would be prolonged. lt might be difficult to calculate BHT of those whiskers. In this study, the difference of the clearance between short whiskers and long whiskers was not examined. lt is necessary to estimate BHT of short whiskers and long whiskers in the further study.

Conclusions:
The fo llowin g things were confirmed from this long-term inhalation study of PT1 :
1. Survival rate and body weight; no difference between exposed and control rats.
2. Biopersistence; prolonged clearance was observed after 1-yr inhalation.
3. Fibrogenicity; mild fibrogenetic potential of alveolar walls and pleura.
4. Carcinogenicity; no malignant tumor, but three adenoma cases and one squamous metaplasia case.
Executive summary:

The pulmonary effects of long-term inhalation of potassium octatttanate whisker (PT1), one of the durable man-made fibers (MMFs), were examined in rats. Male Wistar rats were exposed to PT1 by inhalation for 6 h/day, 5 dayslwk for l yr. The daily average exposure concentration of PT1 aerosol was 2.2 ± 0.7 mg/rnl 111 ± 34 fiber/m/) during the exposure. Rats were sacrificed at 3 days, 6 mo, and 12 mo after l yr of inhalation exposure. The amount of deposited PT1 in rat lungs (lung burden) was 2.4 ± 0.7 mg and the deposition fraction was 7.2% at 3 days after l yr. The clearance of inhaled PT1 after 1 -yr inhalation was prolonged so that the biological half -life time (BHT) was dtfficult to estimate. The histopathological findings showed that mild fibrotic changes were observed around the macrophages that had engulfed the PT1 in the 3-day, 6-mo, and 12-mo rat sacri/ice groups. As for pulmonary tumors, no malignant tumors were observed although 2 adenomas a t 6 mo and l adenoma and l squamous metaplasia at l2 mo after the exposure were found in the rat lungs.

Endpoint:
carcinogenicity: inhalation
Type of information:
other: data from analogue substance
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
The potassium titanates represent a "family" of inorganic substances made by titanium (Ti), oxygen (O) and potassium (K).
The members of this family of substances differ each other in relation to the ratio stoichiometric of the three structural elements within the unit.
The substances are identified and listed below:
- Potassium titanate CAS No. 12030-97-6 (K2TiO3)
- Potassium titanate CAS No. 12056-46-1 (K2Ti2O5)
- Potassium titanate CAS No. 12056-49-4 (K2Ti4O9)
- Potassium titanate CAS No. 12056-51-8 (K2Ti6O13)
- Potassium titanate CAS No. 12056-53-0 (KTi4O8)
- Potassium titanate CAS No. 59766-31-3 (K2Ti8O17)

One of the critical aspects that distinguishes the different substances is the fibrousness of echa specific substances.
These substances are composed by 2 parts: an "amorphous" and a fibrous, in different ratio.

Overall, available data obtained from animal tests, which were performed by inhalation exposure or intratracheal/intraperitoneal administration of the substance, do not show carcinogenic activity. However, the substance may exist both in fibrous and in non-fibrous state.
According to carcinogenic effects recognized for other fibrous materials, the classification in category 2 appears to be justified only if the potassium hexatitanate fibers content is >= 1%.
In the Legal Entity Composition, le fiber content is < 1% and it was classified as not carcinogenic.
Qualifier:
no guideline followed
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
8 wk old
Sex:
male
Route of administration:
inhalation: aerosol
No. of animals per sex per dose:
carcinogenicity group: 10 rats/groups
lung burden gropu: 6 rats/group/time point
lung recovery group: 6 rats/group/time point
Details on study design:
Male Fischer 344 rat, approximately 8 wk old were used in these studies. Each animal was observed twice daily during quarantine to evaluate the health status: only completely healthy animal were placed on study. Wnhin 48 h of animal receipt and again at approximately 3 wk alter arrival sera were collected from randomly selected animnls (10 males) and tested for common rodent viruses and mycoplama and were free of
these pathogens. lnterim serology was also perfomed on rats scheduled to be killed at 6, 12, 18 and 24 months (6 rats/time point) and free of these pahogens. All animals were housed individually in stainless-steel cages during the entire study period.
During recovery period lung recovery animals were housed in wire-bottom cages placed in open racks. During the exposure period cage racks were placed in H-2000 whole-body exposure chambers.
General prodedures for animal care and housing met curret AAALAC standards, current requirements stated in the Guide for Care and Use of Laboratory Animals and by the US Department of Agricolutre through the Animal Welfare Act.
Description (incidence):
The rats were observed observed twice daily during the prestudy and study period for moribundity/mortality.
Description (incidence and severity):
Individual body weight for all rats were recorded within 48 h of recipt and again on the day for randomization.
The body weight and clinical observation of the rats were recorded prior to exposure on study day 1. once a week during the first 13 wk of the study and once of every 4 wk thereafter and at the scheduled necroscopy.
Description (incidence and severity):
It was recorded once a week during the first 13 wk of the study and once every 4 wk thereafter.
Description (incidence and severity):
For hematological evaluations, bloods samples were collected into tubes containing potassium ethylenediamine tetracetic acid EDTA. For serum chemistry evaluations, tubes with no anticoagulant but containing a serum separator gel were used.
Executive summary:

A chronic inhalation toxicity/carcinogenicity study of potassium octatitanate fiber (TISMO) was conducted in male Fbcher Fischer 344 rats. Groups of 135 rats were via whole-body inhalation to 0, 20. 60, or 200 WHO fibers/cc of TISMO,

6 h/day, 5 da)~' " rur 2~ m o. Si'\ or 30 \ubgroup rats "crc killed al'tcr J. 6. 12, IS. ancl 2~ mo ofc,posure ror lung hurdcn C\aluations. Another JO ·ubgroup rats ''ere remo, cd l'rom lhe c\pusure chamber\ after 6 mu or cxposure, placcd in clean air, and rrom thil. gruup 6 rat ~ \\ere 1-..illed al 3, 6. 9, 12, and Il! mo later lo sludy lung clearance. The remaining 75 rat' in cach group ''ere subjccted tu 2~ mn or C'\po,ure l'or chronic to,icit)' and carcinogcnicil) '>IUd) . Rat' C\posed to HEPA-fìltered air (chamber conlrol) ''ere used as a negathe control in cach ' tudy. The lung burden rcsults indicatcd that a t ime point of equilibrium between lung burdcn and lung clearance al 20 WHO fiber~fcc C\· po\ure \\3S attained after apprll\imately IX mo of c\pu!>ure. There \13!> no differencc in the number nr WHO fiber from the lun)!\ bet\\een 18 and 2~ mo al 20 WIIO fiber,{cc C'\pO,urc. But di ~proportio n al rapid in crea~e in lung burden al 200 WUO lìbcr!>/cc C'\Jlll' ure appcarcd lo be '>Hluration of lung clearance rncchani'm re,ultinR from lung 01 crloading. \t 200 \\HO tibcr!>lcc e\po!>ure, appro\imate l ~ 22.9 and 70.5 million WHO fibers \\ere retained in the lung arter J and 6 mo of e\pos ure, res pecth e f~ . but lung'i re, ca led norma l in appearance. Uo\\ c\Cr, ah colar \\ali~ enclo~ing aggrega led T ISVIO-Iadcn ah colar macrophages (A ~Is) sho\\cd fìbrotic thicl..ening and apprO\ Ìmatef.' 197.J million \'t HO fibcrs \\ere retained in thc lung' after 18 rnu or C\posure. lnhaled fibcr'i \\ ere rapidi~ clcared during J- and 6-mo reco\Cr)' pcriod,, and thcreaflcr graduali~· progresshe fibcr rcduction \\a\ ob~ened throughoul 18 mo or reco, e r~ . The number of WHO fibers decrea'led b) appro\imatcl~ 72%, 74%, and 79'k in thc 200.60, an d 20 WHO fìber~/cc groups, rc-.pccli\cl), al thc end of thc 18-mo reco1Cr) peri od foll o" ing 6 mo of exposure. Although in ha led T IS\10 ti ber, in the 20\\ BO tìbcr~/cc c~ posure group " ere phagocytized by ah·eolar macrophage' (,\1\.hl the lung morpholo~Q appeared normaf throughout 2~ mo ore~posure. A t 60 WBO fibers/cc C\posure, a slight dose- an d time-dependenl increa,e in TJ, MO-Iaden AMs wa~ obsened throughout 3, 6. and 12 1110 of C' PO!ture and snmc ah coli containing aggregated T I MO-Iaden A 1\h !>hO\\ l!d ah colar walf thicl..ening al Il! 1110 of C\posurc and mini mal alveolar fìbro.,i'i a t 2~ mo of C'\pO~ ur e. The exposure conccntration i'> intcrprcted a~ a borderline effcct le~e l. Al 200 WIIO li bcr,/cc C\pO,ure, lun g~ pre,cned normal architecture a t J and 6 mo of e\poo,urc. Some ah colar \l ali., enclosing aggregai es of TIS\10-faden A h " ere ,lightl) thicl..ened afler Il mo of C\posure and re, ealed slight ah colar fìbru\i'> after 18 and 2~ mo of e'posurc. 'lcither e'\po\urc related-pulmonar~ neoplasm nor me!lothefi oma "as obsened in 2~ m o of C'\posure. Thc 20 \\HO fibcr'> fcc c\posurc conccntration io, con,idcred tu be a no-obsenable-ad\erse-effect le, el ('\OAELJ. TI \10 c\po~ ure limiU. of l \\IlO fiber/cc \\Ould noi impose a significant hcalth ha1ard lo human, in the \\ Orkplace based on thc animai c\ peri meni'> an d medicai su n C)., un "url..cr\.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Overall, available data obtained from animal tests, which were performed by inhalation exposure or intratracheal/intraperitoneal administration of the substance, do not show carcinogenic activity. However, the substance may exist both in fibrous and in non-fibrous state.

According to carcinogenic effects recognized for other fibrous materials, the classification in category 2 appears to be justified only if the potassium hexatitanate fibers content is >= 1%.

Considering that the tested substances were judged as quite similar each other and to Potassium hexatitanate, the relative quantity of whisker in the tested sample was the crucial parameter in the assessment of the Cancerogenicity of Potassium hexatitanate (composition profile with less than 1% of fiber).

It was possible to conclud that, if the level of fiber is very low (less than 1% of fiber), the substance has not cancerogenic properties.

Additional information

The potassium titanates represent a "family" of inorganic substances made by titanium (Ti), oxygen (O) and potassium (K).

The members of this family of substances differ each other in relation to the ratio stoichiometric of the three structural elements within the unit.

The substances are identified and listed below:

- Potassium titanate CAS No. 12030-97-6 (K2TiO3)

- Potassium titanate CAS No. 12056-46-1 (K2Ti2O5)

- Potassium titanate CAS No. 12056-49-4 (K2Ti4O9)

- Potassium titanate CAS No. 12056-51-8 (K2Ti6O13)

- Potassium titanate CAS No. 12056-53-0 (KTi4O8)

- Potassium titanate CAS No. 59766-31-3 (K2Ti8O17)

One of the critical aspects that distinguishes the different substances is the fibrousness of echa specific substances.

These substances are composed by 2 parts: an "amorphous" and a fibrous, in different ratio.

In particular, the fiber content can be influenced by the choice of raw materials used in the manufacturing process.

According to Lee et al. (1981), rats, hamsters, and guinea pigs were exposed by inhalation to different concentrations of potassium octatitanate fibers. Following 3 months of exposure, the animals were sacrificed between the 15th and 24th month. The exposed animals showed dose-related dust deposition and pulmonary fibrosis mainly in the respiratory bronchiolar region. Most short fibers (<5 µg) were phagocytized by alveolar macrophages, but long fibers ) were phagocytized by foreign body giant cells. Dust-laden macrophages (dust cells) entered into the lumen of bronchiallymphatic or pulmonary blood vessels. Numerous dust cells were transported from the lung to the tracheobronchial and mediastinal lymph nodes where some dust cells penetrated into the blood or lymphatic circulation. Massive direct cell migration of the mediastinal adipose tissue from the lymph nodes occurred occasionally. Dust-laden giant cells were found only occasionally in the liver, and there was widespread migration of the fibers into other vital organs and tissues without any significant responses.

According to Ikegami et al. (2000), 140 male and 140 female rats were divided into 1 control and 3 test groups of 35 rats each, per sex, and exposed by whole-body inhalation to test compound at target concentrations of 0, 1 mg/m3 (1700 fibers/ cm3, 123 WHO fibers/ cm3) ,

10 mg/m3 ( 5900 fibers/ cm3, 952 WHO fibers/ cm3) , and 100 mg/m3 (112,700 fibers/cm3, 7440 WHO fibers/ cm3) for 6 h/ day, 5 days/ wk for 13 wk. Ten rats from each group were killed after 13 wk of exposure and 13 wk of recovery, respectively, forhistopathological evaluation. The other 15 rats from each group were killed to study lung clearance after 91 days of exposure, and approximately 1.5 and 3 mo of recovery following the end of the 13 wk of exposure. The mean fiber length of the chamber atmosphere was 2.8, 2.7, and 2.8μm, while the mean fiber width was 0.48, 0.48, and 0.45μm for the 1-, 10-, and 100-mg/m3 chambers, respectively. In the 1-mg/m3 (123

WHO fibers/ cm3) exposure group, inhaled particles were mostly retained in a few fiber laden alveolar macrophages (AMs) within the alveoli adjacent to alveolar ducts without any adverse tissue response throughout 13 wk of exposure and following 13 wk of

recovery. This exposure concentration was considered to be a no-observable-adverse effect level (NOAEL , since the alveoli containing fiber-laden AMs preserved normal structure. After 13 wk of exposure to 10 mg/m3 ( 952 WHO fibers/ cm3) , fiber-laden AMs were mainly retained at the alveoli adjacent to the alveolar ducts. Infrequently, slight fibrotic thickening was observed in the alveolar ducts and adjoining alveoli, with proliferating fibroblasts and hyperplastic Type II pneumocytes, and microgranulomas.

Occasionally, trace amounts of collagenous material were deposited in the thickened alveolar ducts and adjoining alveolar walls. In addition, minimal alveolar bronchiolarization was occasionally found in the alveoli adjacent to the terminal bronchioles. The peribronchial lymphoid tissue and thymic lymph nodes contained migrated fiber-laden AMs. After 13 wk of recovery, fiber-laden AMs had mostly disappeared from alveoli located in the peripheral acini, but they localized in the alveolar ducts region, suggesting there was active lung clearance of fibers by the AMs via airways. Thickened alveolar ducts and adjacent alveoli were decreased in thickness, a reversible change manifested by reduction of proliferating Type II pneumocytes and fibroblasts. Collagenized fibrosis was slightly more pronounced in the thickened alveolar ducts and adjoining alveoli. The lung response following 13 wk of exposure to 100 mg/m3 (7440 WHO fibers/cm3) and after 13 wk of recovery was similar to those findings of the 952 WHO fibers/cm3 group but more pronounced, demonstrating a clear concentration-related response. Alveolar ducts and adjoining alveolar walls in the central acini were irregularly thickened with more frequent evidence of minimal collagenized fibrosis. The lung burden and clearance of fibers were estimated by measuring the total content of titanium (Ti) in the lungs, but high variability of Ti content in control and exposed groups prevented meaningful lung clearance analysis.

A chronic inhalation toxicity/carcinogenicity study of potassium octatitanate fibers (TISMO) was conducted in male Fischer 344 rats in a study performed by Ikegami et al. (2004). Groups of 135 rats were exposed via whole-body inhalation to 0, 20, 60, or 200 WHO fibers/cc of TISMO, 6 h/day, 5 days/w for 24 mo. Six of 30 subgroup rats were killed after 3, 6, 12, 18, and 24 mo of exposure for lung burden evaluations. Another 30 subgroup rats were removed from the exposure chambers after 6 mo of exposure, placed in clean air, and from this group 6 rats were killed at 3, 6, 9, 12, and 18 mo later to study lung clearance. The remaining 75 rats in each group were subjected to 24 mo of exposure for chronic toxicity and carcinogenicity study. Rats exposed to HEPA-filtered air (chamber control) were used as a negative control in each study. The lung burden results indicated that a time point of equilibrium between lung burden and lung clearance at 20 WHO fibers/cc exposure was attained after approximately 18 mo of exposure. There was no difference in the number of WHO fiber from the lungs between 18 and 24 mo at 20 WHO fibers/cc exposure. But disproportional rapid increase in lung burden at 200 WHO fibers/cc exposure appeared to be saturation of lung clearance mechanism resulting from lung overloading. At 200 WHO fibers/cc exposure, approximately 22.9 and 70.5 million WHO fibers were retained in the lung after 3 and 6 mo of exposure, respectively, but lungs revealed normal in appearance. However, alveolar walls enclosing aggregated TISMO-laden alveolar macrophages (AMs) showed fibrotic thickening and approximately 197.3 million WHO fibers were retained in the lungs after 18 mo of exposure. Inhaled fibers were rapidly cleared during 3- and 6-mo recovery periods, and thereafter gradually progressive fiber reduction was observed throughout 18 mo of recovery. The number of WHO fibers decreased by approximately 72%, 74%, and 79% in the 200, 60, and 20 WHO fibers/cc groups, respectively, at the end of the 18-mo recovery period following 6 mo of exposure. Although inhaled TISMO fibers in the 20 WHO fibers/cc exposure group were phagocytized by alveolar macrophages (AMs) the lung morphology appeared normal throughout 24 mo of exposure. At 60 WHO fibers/cc exposure, a slight dose- and time-dependent increase in TISMO-laden AMs was observed throughout 3, 6, and 12 mo of exposure and some alveoli containing aggregated TISMO-laden AMs showed alveolar wall thickening at 18 mo of exposure and minimal alveolar fibrosis at 24 mo of exposure. The exposure concentration is interpreted as a borderline effect level. At 200 WHO fibers/cc exposure, lungs preserved normal architecture at 3 and 6 mo of exposure. Some alveolar walls enclosing aggregates of TISMO-laden AMs were slightly thickened after 12 mo of exposure and revealed slight alveolar fibrosis after 18 and 24 mo of exposure. Neither exposure related-pulmonary neoplasm nor mesothelioma was observed in 24 mo of exposure. The 20 WHO fibers/cc exposure concentration is considered to be a no-observable-adverse-effect level (NOAEL). TISMO exposure limits of 1 WHO fiber/cc would not impose a significant health hazard to humans in the workplace based on the animal experiments and medical surveys on workers.

At least, the pulmonary effects of long-term inhalation of potassium octatitanate whisker (PT1), one of the durable man-made fibers (MMFs), were examined inrats (Yamato et al. 2003). Male Wistarratswere exposed to PT1 byinhalationfor 6 h/day, 5 days/wk for 1 yr. The daily average exposure concentration of PT1 aerosol was 2.2 +/- 0.7 mg/m3 (111 +/- 34 fiber/ml) during the exposure.Ratswere sacrificed at 3 days, 6 mo, and 12 moafter1 yr ofinhalationexposure. The amount of deposited PT1 in rat lungs (lung burden) was 2.4 +/- 0.7 mg and the deposition fraction was 7.2% at 3 daysafter1 yr. Theclearanceof inhaled PT1after1-yrinhalationwas prolonged so that the biological half-life time (BHT) was difficult to estimate. The histopathological findings showed that mild fibrotic changes were observed around the macrophages that had engulfed the PT1 in the 3-day, 6-mo, and 12-mo rat sacrifice groups. As forpulmonarytumors, no malignant tumors were observed, although 2 adenomas at 6 mo and 1 adenoma and 1 squamous metaplasia at 12 moafterthe exposure were found in the rat lungs.