Registration Dossier
Registration Dossier
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 601-472-6 | CAS number: 117314-20-2
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics, other
- Type of information:
- other: A paper-based toxicokinetics assessment by a qualified toxicologist based on summaries of studies on the substance and literature.
- Adequacy of study:
- key study
- Study period:
- 5.7.2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Remarks:
- In accordance with Annex VIII (point 8.8) of Regulation (EC) No 1907/2006 (REACH), a paper-based toxicokinetics assessment has been conducted by a qualified toxicologist based on summaries of studies on the substance and literature. The assessment of the likely toxicokinetic behaviour of the substance is provided to the extent that can be derived from the relevant available information at the time of the assessment. The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, November 2014).
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
- Principles of method if other than guideline:
- The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, November 2014). In accordance with Annex VIII (point 8.8) of Regulation (EC) No 1907/2006 (REACH), a paper-based toxicokinetics assessment has been conducted for the substance by a qualified toxicologist.
- GLP compliance:
- no
- Conclusions:
- The available information suggests that absorption of the test substance from the gastrointestinal tract will be limited. Dermal absorption is also considered to be limited. Any substance that is absorbed is unlikely to be widely distributed. Biliary excretion is likely to be the significant route of excretion. Experimental toxicokinetic studies were not available.
- Executive summary:
In accordance with Annex VIII (point 8.8) of Regulation (EC) No 1907/2006 (REACH), a paper-based toxicokinetics assessment was conducted by a qualified toxicologist based on summaries of studies on the substance and literature. The assessment of the likely toxicokinetic behaviour of the substance was provided to the extent that can be derived from the relevant available information at the time of the assessment. Experimental toxicokinetic studies were not available.
The available information suggests that the substance is not readily available for absorption via the oral route but limited absorption may be possible. This is supported by the physico-chemical properties of the substance and by available toxicological data. Any substance absorbed is unlikely to be widely distributed. Biliary excretion is considered to be the significant route of excretion for the substance.
Reference
Toxicokinetic behaviour
The substance is a white granular solid and the molecular weight is 843 g/mol. The substance is highly insoluble in water. The substance has a low vapour pressure value (calculated as <1.2x 10^-9 Pa at 25°C), is not highly flammable and does not have explosive or oxidising properties. It is therefore considered to be of low volatility. The percentage of the test item having an inhalable particle size of less than 100 μm was determined to be 2.92%. The test item has been considered to be essentially non-inhalable.
The available repeated dose reproductive OECD 422 screening study (oral route) showed no toxicologically significant treatment-related effects. The oral administration of the substance to rate by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day was tolerated well. The study therefore showed minimal evidence of significant absorption of the substance.
The acute toxicity studies via oral and dermal routes showed no signs of systemic toxicity. The substance is not a skin sensitiser or skin irritant, but is considered to be an eye irritant. The substance gave negative results in three appropriate in vitro genotoxicity studies in either the presence or absence of an auxiliary metabolising system.
Absorption
Results of the repeated dose reproductive OECD 422 screening study (oral route) showed limited evidence of significant gastric absorption of the test item. The relatively large molecular size of the substance may also limit the amount of absorption through passive diffusion. However, the gastro-intestinal tract may provide a limited route of absorption, following oral administration, before entering the circulatory system via the blood.
It is considered that absorption via the skin will also be limited due to the molecular size of the substance. An acute dermal toxicity study showed no signs of systemic toxicity, so did not show evidence of substantial dermal absorption. As the substance is not a skin corrosive or irritant, potential dermal absorption will not be increased by damage to the skin at point of contact.
Inhalation is not considered to be a significant route of exposure based on the low volatility of the substance and particle size.
Distribution
Substantial systemic distribution of the substance is not evident from the repeated dose reproductive OECD 422 screening study and acute toxicity studies (oral and dermal) due to lack of systemic effects and lack of changes observed in hematology, blood chemistry, organ weights and histopathology.
The substance is highly insoluble and is unlikely to be absorbed unchanged. If absorbed it is likely that the substance is not distributed widely. The substance is not a skin sensitiser (based on results of a LLNA study). This suggests that the substance does not bind to carrier proteins in the circulatory system.
Metabolism
The results of the repeated dose reproduction OECD 422 screening study did not show any evidence of adaptive response in the liver of rats, so there is no evidence of enhanced metabolism. The results of the genotoxicity assays showed that genotoxicity is neither enhanced or diminished in the presence of the S9 metabolising system.
Excretion
Poorly-water soluble substances are not favourable for urinary excretion and therefore biliary excretion may well be a significant route for this substance. There is no evidence from the available studies to suggest enhanced heptatic metabolism to suggest urinary excretion is a significant route of excretion. Any substance that is not adsorbed from the gut will be excreted in the faeces.
Description of key information
Experimental toxicokinetic studies are not available. A paper-based toxicokinetics assessment concludes the following: dermal absorption and absorption of the test substance from the gastrointestinal tract considered to be limited. Any substance that is absorbed is unlikely to be widely distributed. Biliary excretion is likely to be the significant route of excretion.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
- Absorption rate - oral (%):
- 10
- Absorption rate - dermal (%):
- 0
- Absorption rate - inhalation (%):
- 0
Additional information
A paper-based toxicokinetics assessment was conducted based on available studies on the substance and literature. The assessment of the likely toxicokinetic behaviour of the substance was provided to the extent that can be derived from the relevant available information at the time of the assessment. Experimental toxicokinetic studies were not available.
Toxicokinetic behaviour
The substance is a white granular solid and the molecular weight is 843 g/mol. The substance is highly insoluble in water. The substance has a low vapour pressure value (calculated as <1.2x 10^-9 Pa at 25°C), is not highly flammable and does not have explosive or oxidising properties. It is therefore considered to be of low volatility. The percentage of the test item having an inhalable particle size of less than 100 μm was determined to be 2.92%. The test item has been considered to be essentially non-inhalable.
The available repeated dose reproductive OECD 422 screening study (oral route) showed no toxicologically significant treatment-related effects. The oral administration of the substance to rate by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day was tolerated well. The study therefore showed minimal evidence of significant absorption of the substance.
The acute toxicity studies via oral and dermal routes showed no signs of systemic toxicity. The substance is not a skin sensitiser or skin irritant, but is considered to be an eye irritant. The substance gave negative results in three appropriate in vitro genotoxicity studies in either the presence or absence of an auxiliary metabolising system.
Absorption
Results of the repeated dose reproductive OECD 422 screening study (oral route) showed limited evidence of significant gastric absorption of the test item. The relatively large molecular size of the substance may also limit the amount of absorption through passive diffusion. However, the gastro-intestinal tract may provide a limited route of absorption, following oral administration, before entering the circulatory system via the blood.
It is considered that absorption via the skin will also be limited due to the molecular size of the substance. An acute dermal toxicity study showed no signs of systemic toxicity, so did not show evidence of substantial dermal absorption. As the substance is not a skin corrosive or irritant, potential dermal absorption will not be increased by damage to the skin at point of contact.
Inhalation is not considered to be a significant route of exposure based on the low volatility of the substance and particle size.
Distribution
Substantial systemic distribution of the substance is not evident from the repeated dose reproductive OECD 422 screening study and acute toxicity studies (oral and dermal) due to lack of systemic effects and lack of changes observed in hematology, blood chemistry, organ weights and histopathology.
The substance is highly insoluble and is unlikely to be absorbed unchanged. If absorbed it is likely that the substance is not distributed widely. The substance is not a skin sensitiser (based on results of a LLNA study). This suggests that the substance does not bind to carrier proteins in the circulatory system.
Metabolism
The results of the repeated dose reproduction OECD 422 screening study did not show any evidence of adaptive response in the liver of rats, so there is no evidence of enhanced metabolism. The results of the genotoxicity assays showed that genotoxicity is neither enhanced or diminished in the presence of the S9 metabolising system.
Excretion
Poorly-water soluble substances are not favourable for urinary excretion and therefore biliary excretion may well be a significant route for this substance. There is no evidence from the available studies to suggest enhanced heptatic metabolism to suggest urinary excretion is a significant route of excretion. Any substance that is not adsorbed from the gut will be excreted in the faeces.
Bioaccumulation potential
The substance can be considered to have no bioaccumulation potential as it has a very low solubility in water and negligible lipophilicity. Due to the low solubility, the substance will be released to solution (e.g. bowel contents) only very slowly. As it has a low likelihood of passing through biological membranes, systemic exposure to the substance will also be very slow and very limited. There is no reason for the elimination of the substance to be slower than its access to the body, meaning that no bioaccumulation of the substance is expected.
As the substance is inorganic, no partition coefficient has been determined. However, it is known that the sodium ion in the molecule is exchangeable, but that the titanium oxide structure in itself is very stable. Titanium will not be released from the molecule, and based on the results of the aquatic toxicity testing it is also possible to assume that titanium is not going to be highly bioavailable. Based on the results of the aquatic toxicity testing it can also be concluded that there is nothing toxicologically significant that could be accumulated into aquatic organisms from the substance.
Absorption rates
The oral absorption rate for the substance has been estimated as 10 %, due to the fact that the substance has a high molecular weight (843) meaning that it is not assumed to be absorbed by the oral route, it is highly insoluble in water and has a large particle size (2.92% of particles <100 µm). The oral LD50 for the substance is >2000 mg/kg and there were no acute systemic effects, nor any systemic effects in the OECD 422 study.
The dermal absorption rate for the substance has been estimated as 0 %, due to the fact that the substance has a high molecular weight (843), meaning that it cannot pass the corneal layer and therefore the potential for absorption through the skin can be regarded as negligible. The substance is furthermore highly insoluble in water and has a large particle size (2.92% of particles <100 µm). The dermal LD50 for the substance is >2000 mg/kg and there were no acute systemic effects after dermal exposure, nor any systemic effects in the OECD 422 study. Furthermore, results for skin corrosion, irritation and sensitization were negative.
The inhalatory absorption rate for the substance has been estimated as 0 %, due to the fact that the substance has a very low vapour pressure (< 1.2 x 10^-9 Pa) and a large particle size (2.92% of particles <100 µm), excluding any likely exposure through inhalation. The substance also has a high molecular weight (843), meaning that it is not assumed to be absorbed by the inhalation route.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
