Dipotassium titanate(2-)

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Justification for type of information:

A chronic inhalation toxicity and carcinogenicity study was performed for industrial health and safety of production workers and users.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Version / remarks:

1981

Deviations:

yes

Remarks:

Only males were tested

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Dipotassium titanate(2-)

EC Number:

261-919-2

EC Name:

Dipotassium titanate(2-)

Cas Number:

59766-31-3

Molecular formula:

K2O17Ti8

IUPAC Name:

dipotassium titanate(2-)

Test material form:

solid: crystalline

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Core study: 105 weeks
Lung burden: Lungs from 6 males/group/timepoint were evaluated for lung fiber burden analysis at 3, 6, 12, 18 and 24 months after exposure start.

Frequency of treatment:

6 hours/day, 5 days/week

Post exposure period:

Lung recovery study: 30 males/group were exposed for 26 weeks and then moved to a holding room for a recovery period. Lungs from 6 males/group/timepoint were evaluated at 3, 6, 9, 12 and 18 months after termination of exposure

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

20 other: WHO-defined fibres/cc

Doses / concentrations 2

Dose / conc.:

60 other: WHO-defined fibres/cc

Doses / concentrations 3

Dose / conc.:

200 other: WHO-defined fibres/cc

No. of animals per sex per dose:

Core study 75 males/group
Lung burden study: 30 males/group
Lung recovery study 30 males/group

Applicant's summary and conclusion

Executive summary:

A 2 -year inhalation study combined with determination of lung burden and fibre clearance was performed with TISMO-D in accordance with GLP principles. Groups of 135 Fischer F334 male rats were exposed to 0, 20, 60 or 200 WHO fibres/mL 6h/day, 5 days/week for 24 months. 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.

The results indicated that at 20 fibres/mL the steady state of lung bruden (equilibrium between lung burden and clearance) was reached after approximately 18 months of exposure. At all times investigated, 200 fibres/mL resulted in a disproportional increase in lung burden indicating saturation of lung clearance as a result of overloading, while a graduate increase was seen at 20 or 60 fibres/mL. To determine lung clearance, subgroups were removed after 6 months of exposure and were killed 3, 6, 12 and 18 months later. Following the 6 -month exposure, the amount of fibres in the lung decreased with a half-life of approximately 6 months at all exposures and was decreased by approximately 72%, 74% and 79% in the 200, 60 and 20 WHO fibres/mL groups, respectively.

TISMO exposure-related histopathological changes were only observed in the lungs and associated bronchial lymph nodes. At 20 WHO fibers/mL exposure, lungs revealed normal alveoli indistinguishable from those of control lungs. At 60 WHO fibres/mL, aggregated TISMO-laden AMs were observed in some alveoli adjacent to alveolar ducts after 18 months of exposure. Some alveolar walls enclosing aggregated TISMO-laden AMs were slightly thickened with proliferating alveolar lining cells (Type II pneumocytes), but lungs maintained normal general architecture. At 200 WHO fibers/cc exposure, some alveolar walls enclosing aggregates of TISMO-D laden alveolar marophages were slightly thickened after 12 months of exposure and revealed slight alveolar fibrosis after 18 months and 24 months of exposure. Based on the results of the lung burden study and histopathological observations, the exposure concentration of 20 WHO fibres/mL was considered a NOAEL. No exposure related pulmonary neoplasm or mesothelioma was observed after 24 months of exposure.

Based on the half-life of about 180 days, the high biopersistence does not exclude carcinogenic potential of this fibre although the study supports the NOAEL of 20 WHO fibres/mL. TISMO-D is therefore classified for carcinogenicity Cat. 2 according to Regulation (EC) 1272/2008 (including all amendments).