Registration Dossier

Administrative data

Description of key information

The repeated toxicity via inhalation route was studied in an in vivo test performed under GLP conditions and according Annex V.

The NOAEL in this study was considered to be 5 mg/m3in the original report, based on the lack of systemic or respiratory tract toxicity at this exposure concentration. The NOAEL addressed in the NONS dossier was 0.5 mg/L/6/h/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Data waiving:
exposure considerations
Justification for data waiving:
other:
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
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:
no data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
The study was performed according to a valid guideline without any deviations and was conducted under GLP conditions. Furthermore, the data were submitted by another legal entity, under Directive 67/548/EEC, at least 12 years previously. The registrant has been granted permission to use the information, which has been extracted from the ECHA databases, for REACH registration purposes. No full information related to the experimental result are available but these deficiencies do not affect the quality of the relevant results.
Qualifier:
according to
Guideline:
other: Annex V
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
no data
Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
no data
Sex:
male/female
Details on test animals and environmental conditions:
no data
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
other: none
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
Method of exposure:
Aerosol
Mass median aerodynamic diameter: 5mg/m3:
500mg/m3:
Mean fibre length = 1.921microm
Mean fibre width = 0.691 microm
Mean fibre length = 2.0111m
Mean fibre width = 0.66 microm
50mg/m3:
Mean fibre lenglh = 1.91microm
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
90 days
Frequency of treatment:
Duration of exposure per day: 6 hours
Dosing regime: 5 days/week
No. of animals per sex per dose:
Male: 50 animals at 0 mg/l
Male: 50 animals at 0.005 mg/l
Male: 50 animals at 0.05 mg/l
Male: 50 animals at 0.5 mg/l
Female: 50 animals at 0 mg/l
Female: 50 animals at 0.005 mg/l
Female: 50 animals at 0.05 mg/l
Female: 50 animals at 0.5 mg/l
Details on study design:
no data
Positive control:
no data
Observations and examinations performed and frequency:
Mortality, clinical observations, bodyweight, Laboratory findings, Blood Chemistry, Urinalysis, Effects in organs, Organ Weights, Histopathology, Lung clearance results.
Sacrifice and pathology:
no data
Other examinations:
no data
Statistics:
no data
Clinical signs:
no effects observed
Description (incidence and severity):
There were no unscheduled animal deaths in this study. No treatment-related clinical findings were observed
Mortality:
no mortality observed
Description (incidence):
There were no unscheduled animal deaths in this study. No treatment-related clinical findings were observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The weight changes in the 0.5 mg/L group are considered to be a non-specific effect, probably related to the high dose response of inhaled foreign material, rather than to any direct specific toxic effect of the compound.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no haematological effects considered treatment-related.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no blood chemistry effects considered treatment-related.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no toxicologically significant urinary effects observed.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
lncreased absolute lung weight values were observed in. m ales at 0.05 mg/l (16%) and both sexes at 0.5 mg/l (59% in males, 20% in females). After a 13 week recovery period, increased lung weights were observed only in the 0.5 mg/l females.
Gross pathological findings:
no effects observed
Description (incidence and severity):
incidental lesions that were not related to exposure.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
no data
Dose descriptor:
NOAEL
Effect level:
0.5 mg/L air
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: exposure duration: 6 hours/day
Critical effects observed:
no
Lowest effective dose / conc.:
0.5 other: mg/L/6/h/day
Treatment related:
no
Dose response relationship:
no
Relevant for humans:
no

Bodyweight:

Mean bodyweights were up to 8% lower than controls in the male low and high exposure and recovery groups and in the female high concentration group. The slight decreases were sporadic in the low exposure group and not consistent in the high exposure group for either sex. The degree of bodyweight loss did not increase with either the fibre concentration or with duration of exposure.

Lung clearance results:

There was a clear, aerosol exposure concentration dependent, increase in total Ti lung content and Ti lung tissue concentration. Rats exposed to 0.005 mg/1 had significantly lower Ti lung levels compared to rats exposed to 0.05 mg/1, which had titanium levels approximately 12 times greater than those exposed at 0.005 mg/1. Rats exposed to 0.5 mg/1 had titanium levels approximately 5 times greater than those exposed at 0.05 mg/1 at the week.post-exposure necropsy.

Background or endogenous Ti lung levels in control rats were approximately 2 orders of magnitude lower than rats exposed to the lowest aerosol concentration (0.005 mg/1).

Effects in organs: Necropsy:

Macroscopic observations in the lungs related to fibre exposure were observed only in the high concentration groups.

Diffuse discolouration of the lungs, was seen in all 0.5 mg/1 group rats after thirteen weeks of exposure and remained present after thirteen weeks of recovery. In these same rats, a number ofthymic lymph nodes or areas of the thymuses appeared to have test substance exposure-related findings consisting of either a focal nodular enlargement and/or discolouration.

In addition one 0.05 mg/1 female and one male and two females exposed at 0.5 mg/1 had bronchiolar lymph nodes that appeared to be enlarged or had a nodule.

Subsequent microscopic examination revealed that these lymphoid tissues were laden with particle filled macrophages.

All other gross observations were spontaneous.

Histopathology

Test substance exposure-related effects at the end of the 13-weeks of treatment were found in the lungs. Distinct concentration dependent histopathology changes consisted of particle-laden macrophages (>=0.005 mg/1) that were intraluminal, as well as, being present within the interstitium of the alveoli. This latter observation, in association with increased numbers of alveolar epithelial

cells and interstitial cells, was the cause for minimal to mild thickening of the alveolar walls at fibre concentrations >= 0.05 mg/1 following exposure, which was also present in the recovery group rats. Although there were occasional focci of interstitial cell proliferation, there was no obvious mature collogen deposition (fibrosis) as determined by conventional hematoxylin and eosin staining.

The multifocal distribution of thickened alveolar walls within both the exposure and recovery groups appeared to be an indication of slight localized irritation caused by the particulate being phagocytized. Little inflammatory response was present. The severity of the thickening of the alveolar walls was not concentration dependent at either the interim or final necropsies and there was no significant evidence of progression of severity of these lesions over the 3 month recovery period.

There was evidence of clearance of particulate material from the lungs in the high concentration groups. During the exposure phase the average severity of the pulmonary particle-laden macrophages for the base rats ranged from minimal (grade 1) in the 0.005 mg/1 group to severe (grade 4) in the 0.5 mg/1 group. Following recovery, the only differente was in the 0.5 mg/1 group rats where the severity for the particle-laden macrophages ranged from moderate

(grade 3) to severe.

A lesion termed alveolar epithelial hyperplasia and characterised as focal hyperplasia of epithelial cells of the alveoli was present in one 0.005 mg/1 group female and one 0.5 mg/1 group male at the conclusion of thirteen of exposure.

A small alveolar/bronchiolar adenoma in the lungs of a 0.05 mg/1 group male allowed to recover 13 weeks after the conclusion of exposure was observed. Although possessing some mitotic figures and infiltrating around a blood vessel, this tumor was viewed as exhibiting expansive growth rather than invasiveness. The presence of a single adenoma in one rat from the mid-exposure level group is inconclusive.

Particle-laden macrophages were present in a few enlarged bronchiolar lymph nodes of 0.5 mg/1 exposed rats and in thymic lymph nodes that were found for exposed-rats. The average severity of the particle-laden macrophages in the thymic lymph nodes was exposure-related and similar to findings in the lungs. These findings are compatible with lymphatic clearence of particulate materia! from the lungs to regionallymph nodes.

Comparison of lung and thymic lymph node findings to those determined during the blind phase of the study revealed very

similar results, indicating that prior knowledge of the concentration groups had not biased the study pathologist.

Conclusions:
The test material does not meet the criteria for classification according to EU classification system (Regulation (EC) No 1272/2008).
Executive summary:

The repeated toxicity was studied in an in vivo test performed under GLP conditions and according Annex V.

The NOAEL in this study was considered to be 5 mg/m3 in the original report, based on the lack of systemic or respiratory tract toxicity at this exposure concentration. The NOAEL addressed in the NONS dossier was 0.5 mg/L/6/h/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
500 mg/m³
Study duration:
subchronic
Species:
rat
System:
respiratory system: lower respiratory tract
Organ:
lungs

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:
no data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
The study was performed according to a valid guideline without any deviations and was conducted under GLP conditions. Furthermore, the data were submitted by another legal entity, under Directive 67/548/EEC, at least 12 years previously. The registrant has been granted permission to use the information, which has been extracted from the ECHA databases, for REACH registration purposes. No full information related to the experimental result are available but these deficiencies do not affect the quality of the relevant results.
Qualifier:
according to
Guideline:
other: Annex V
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
no data
Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
no data
Sex:
male/female
Details on test animals and environmental conditions:
no data
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
other: none
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
Method of exposure:
Aerosol
Mass median aerodynamic diameter: 5mg/m3:
500mg/m3:
Mean fibre length = 1.921microm
Mean fibre width = 0.691 microm
Mean fibre length = 2.0111m
Mean fibre width = 0.66 microm
50mg/m3:
Mean fibre lenglh = 1.91microm
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
90 days
Frequency of treatment:
Duration of exposure per day: 6 hours
Dosing regime: 5 days/week
No. of animals per sex per dose:
Male: 50 animals at 0 mg/l
Male: 50 animals at 0.005 mg/l
Male: 50 animals at 0.05 mg/l
Male: 50 animals at 0.5 mg/l
Female: 50 animals at 0 mg/l
Female: 50 animals at 0.005 mg/l
Female: 50 animals at 0.05 mg/l
Female: 50 animals at 0.5 mg/l
Details on study design:
no data
Positive control:
no data
Observations and examinations performed and frequency:
Mortality, clinical observations, bodyweight, Laboratory findings, Blood Chemistry, Urinalysis, Effects in organs, Organ Weights, Histopathology, Lung clearance results.
Sacrifice and pathology:
no data
Other examinations:
no data
Statistics:
no data
Clinical signs:
no effects observed
Description (incidence and severity):
There were no unscheduled animal deaths in this study. No treatment-related clinical findings were observed
Mortality:
no mortality observed
Description (incidence):
There were no unscheduled animal deaths in this study. No treatment-related clinical findings were observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The weight changes in the 0.5 mg/L group are considered to be a non-specific effect, probably related to the high dose response of inhaled foreign material, rather than to any direct specific toxic effect of the compound.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no haematological effects considered treatment-related.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no blood chemistry effects considered treatment-related.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no toxicologically significant urinary effects observed.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
lncreased absolute lung weight values were observed in. m ales at 0.05 mg/l (16%) and both sexes at 0.5 mg/l (59% in males, 20% in females). After a 13 week recovery period, increased lung weights were observed only in the 0.5 mg/l females.
Gross pathological findings:
no effects observed
Description (incidence and severity):
incidental lesions that were not related to exposure.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
no data
Dose descriptor:
NOAEL
Effect level:
0.5 mg/L air
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: exposure duration: 6 hours/day
Critical effects observed:
no
Lowest effective dose / conc.:
0.5 other: mg/L/6/h/day
Treatment related:
no
Dose response relationship:
no
Relevant for humans:
no

Bodyweight:

Mean bodyweights were up to 8% lower than controls in the male low and high exposure and recovery groups and in the female high concentration group. The slight decreases were sporadic in the low exposure group and not consistent in the high exposure group for either sex. The degree of bodyweight loss did not increase with either the fibre concentration or with duration of exposure.

Lung clearance results:

There was a clear, aerosol exposure concentration dependent, increase in total Ti lung content and Ti lung tissue concentration. Rats exposed to 0.005 mg/1 had significantly lower Ti lung levels compared to rats exposed to 0.05 mg/1, which had titanium levels approximately 12 times greater than those exposed at 0.005 mg/1. Rats exposed to 0.5 mg/1 had titanium levels approximately 5 times greater than those exposed at 0.05 mg/1 at the week.post-exposure necropsy.

Background or endogenous Ti lung levels in control rats were approximately 2 orders of magnitude lower than rats exposed to the lowest aerosol concentration (0.005 mg/1).

Effects in organs: Necropsy:

Macroscopic observations in the lungs related to fibre exposure were observed only in the high concentration groups.

Diffuse discolouration of the lungs, was seen in all 0.5 mg/1 group rats after thirteen weeks of exposure and remained present after thirteen weeks of recovery. In these same rats, a number ofthymic lymph nodes or areas of the thymuses appeared to have test substance exposure-related findings consisting of either a focal nodular enlargement and/or discolouration.

In addition one 0.05 mg/1 female and one male and two females exposed at 0.5 mg/1 had bronchiolar lymph nodes that appeared to be enlarged or had a nodule.

Subsequent microscopic examination revealed that these lymphoid tissues were laden with particle filled macrophages.

All other gross observations were spontaneous.

Histopathology

Test substance exposure-related effects at the end of the 13-weeks of treatment were found in the lungs. Distinct concentration dependent histopathology changes consisted of particle-laden macrophages (>=0.005 mg/1) that were intraluminal, as well as, being present within the interstitium of the alveoli. This latter observation, in association with increased numbers of alveolar epithelial

cells and interstitial cells, was the cause for minimal to mild thickening of the alveolar walls at fibre concentrations >= 0.05 mg/1 following exposure, which was also present in the recovery group rats. Although there were occasional focci of interstitial cell proliferation, there was no obvious mature collogen deposition (fibrosis) as determined by conventional hematoxylin and eosin staining.

The multifocal distribution of thickened alveolar walls within both the exposure and recovery groups appeared to be an indication of slight localized irritation caused by the particulate being phagocytized. Little inflammatory response was present. The severity of the thickening of the alveolar walls was not concentration dependent at either the interim or final necropsies and there was no significant evidence of progression of severity of these lesions over the 3 month recovery period.

There was evidence of clearance of particulate material from the lungs in the high concentration groups. During the exposure phase the average severity of the pulmonary particle-laden macrophages for the base rats ranged from minimal (grade 1) in the 0.005 mg/1 group to severe (grade 4) in the 0.5 mg/1 group. Following recovery, the only differente was in the 0.5 mg/1 group rats where the severity for the particle-laden macrophages ranged from moderate

(grade 3) to severe.

A lesion termed alveolar epithelial hyperplasia and characterised as focal hyperplasia of epithelial cells of the alveoli was present in one 0.005 mg/1 group female and one 0.5 mg/1 group male at the conclusion of thirteen of exposure.

A small alveolar/bronchiolar adenoma in the lungs of a 0.05 mg/1 group male allowed to recover 13 weeks after the conclusion of exposure was observed. Although possessing some mitotic figures and infiltrating around a blood vessel, this tumor was viewed as exhibiting expansive growth rather than invasiveness. The presence of a single adenoma in one rat from the mid-exposure level group is inconclusive.

Particle-laden macrophages were present in a few enlarged bronchiolar lymph nodes of 0.5 mg/1 exposed rats and in thymic lymph nodes that were found for exposed-rats. The average severity of the particle-laden macrophages in the thymic lymph nodes was exposure-related and similar to findings in the lungs. These findings are compatible with lymphatic clearence of particulate materia! from the lungs to regionallymph nodes.

Comparison of lung and thymic lymph node findings to those determined during the blind phase of the study revealed very

similar results, indicating that prior knowledge of the concentration groups had not biased the study pathologist.

Conclusions:
The test material does not meet the criteria for classification according to EU classification system (Regulation (EC) No 1272/2008).
Executive summary:

The repeated toxicity was studied in an in vivo test performed under GLP conditions and according Annex V.

The NOAEL in this study was considered to be 5 mg/m3 in the original report, based on the lack of systemic or respiratory tract toxicity at this exposure concentration. The NOAEL addressed in the NONS dossier was 0.5 mg/L/6/h/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Data waiving:
exposure considerations
Justification for data waiving:
other:
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Data waiving:
exposure considerations
Justification for data waiving:
other:
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Reason / purpose:
exposure-related information
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

no data

Justification for classification or non-classification