Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Read across concept

Synthetic rutile consists primarily of a titanate phase (solid solution) most of which is titanium in an oxidised form. Upon ingestion, a low rate of dissolution in the GI tract is assumed, based on the experimental verified inertness of the material. Any material being released from Synthetic rutile under physiological conditions will be in the form of ionic titanium, which is similarly the case for titanium dioxide, thus read-across from repeated dose oral toxicity data on titanium dioxide is considered feasible without any restrictions.

Furthermore, transformation/dissolution testing according to “OECD 29 Environmental Health and Safety Publications, Series on testing and assessment, Guidance document on transformation/ dissolution of metals and metal compounds in Aqueous media” has shown that synthetic rutile compared to titanium dioxide has a similar release rate of titanium ions (please refer to the respective entry under the endpoint water solubility).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
700 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: See the discussion below.
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEL
DNEL value:
3 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not applicable
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Read across concept

Synthetic rutile consists primarily of a titanate phase (solid solution) most of which is titanium in an oxidised form. Upon ingestion, a low rate of dissolution in the GI tract is assumed, based on the experimental verified inertness of the material. Any material being released from Synthetic rutile under physiological conditions will be in the form of ionic titanium, which is similarly the case for titanium dioxide, thus read-across from repeated dose oral toxicity data on titanium dioxide is considered feasible without any restrictions.

Furthermore, transformation/dissolution testing according to “OECD 29 Environmental Health and Safety Publications, Series on testing and assessment, Guidance document on transformation/ dissolution of metals and metal compounds in Aqueous media” has shown that synthetic rutile compared to titanium dioxide has a similar release rate of titanium ions (please refer to the respective entry under the endpoint water solubility).

The available data on titanium dioxide in rats and mice clearly suggest that ingested titanium dioxide is neither toxic nor carcinogenic to both species

In the NCI carcinogenicity study, Fischer 344 rats and B6C3F1 mice were fed diets containing 0, 25000 and 50000 ppm titanium dioxide for 103 weeks (NCI 1979). Based on the histopathological examination, titanium dioxide was considered to be neither toxic nor carcinogenic to rats and mice. Thus, the highest dietary concentration of 50000 ppm titanium dioxide is representing the NOAEL which corresponds to a dose of 3500 mg titanium dioxide/kg bw/d for rats.

Therefore, the oral NOAEL of 3500 mg of titanium dioxide/kg bw/d for chronic toxicity in rats is used as dose descriptor for the calculation of a DNEL for systemic effects for humans exposed orally to different formulations of Titanium dioxide.

Application of assessment factors

The following aspects were taken into account: inter-species variability (extrapolation from animal data to humans), intra-species variability (variability in chemical sensitivity within humans), differences in duration of exposure, issues related to dose-response, and quality of the whole database.

Inter-species variability:

- correction for differences in metabolic rate (AS)*: 1

- remaining differences (e.g. toxicokinetics/-dynamics): 1

Intra-species variability:

- general population: 5**

Exposure duration:

- chronic exposure: 1

Dose response:

- adequate data available: 1

Quality of whole data base:

- no need for a further assessment factor: 1

Overall: 5

*: factor for allometric scaling

**: This assessment factor is introduced since it is expected that a greater variability in response from the most to least sensitive human would be seen, relative to an experimental animal population. ECETOC (2003) has reviewed scientific literature on the distribution of human data for various toxicokinetic and toxicodynamic parameters to assess intra-species variability within the human population, specifically by Renwick and Lazarus (1998) and Hattis et al. (1999). Considering that the data analysed by these authors includes both sexes, a variety of disease states and ages, the use of the 95th percentile of the distribution of the variability for these datasets is considered sufficiently conservative to account for intra-species variability for the general population. Based on this, a default assessment factor of 5 is recommended by ECETOC (2003) (please also refer to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health, table R.8-19 on page 76).

There is substance-specific data available for inter-species variability: a toxicokinetic study in rats with oral administration of Titanium dioxide demonstrated that no absorption of Titanium dioxide from the gastrointestinal tract and no accumulation in organ tissues occurred thus indicating no systemic availability (Landford-Pollard, 2003). Moreover, any metabolism of Titanium dioxide as inorganic material can be excluded. There are no reasons to assume that this behaviour which is based on the physico-chemical properties of the substance will be different between rats and humans. Therefore, it is considered to be justified to apply substance-specific assessment factors accounting for a correction for differences in metabolic rate of 1 and for remaining differences of 1 instead of using the respective default factors of 4 and 2.5, respectively.