Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
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: 236-675-5 | CAS number: 13463-67-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu./o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Endpoint summary
Administrative data
Description of key information
Acute toxicity, oral: LD50 > 5000mg/kg bw
Acute toxicity, inhalation: LC50 > 6,82mg/L (MMAD=1.55 µm, GSD=1.70 µm)
Acute toxicity, dermal: Conduct of an acute dermal toxicity study is unjustified as inhalation of the substance is considered as major route of exposure and physicochemical properties and dermal absorption data of the substance do not suggest a significant rate of absorption through the skin (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).
Key value for chemical safety assessment
Acute toxicity: via oral route
Link to relevant study records
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP-Guideline study, however basic data of test item (purity, stability) are missing.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 401 (Acute Oral Toxicity)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.1 (Acute Toxicity (Oral))
- GLP compliance:
- yes
- Test type:
- standard acute method
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK)
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 227-243 g (males) and 200-214 g (females)
- Fasting period before study:
- Housing: The animals were housed in groups of up to 5 by sex in solid-floor polypropylene cages furnished with woodflakes.
- Diet: ad libitum; with the exception of an overnight fast immediately before dosing
- Water: ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22
- Humidity (%): 50-56
- Air changes (per hr): 15
- Photoperiod: 12 hours dark/light cycle - Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Details on oral exposure:
- The volume administered to each animal was calculated according to its fasted body weight at the time of dosing.
- Doses:
- Based on the results of a range-finding study a group of animals was treated as follows:
Dose level: 2000 mg/kg
Concentration: 200 mg/ml
Dose volume: 10 ml/kg - No. of animals per sex per dose:
- 5 males and 5 females
- Control animals:
- not specified
- Details on study design:
- The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days. Individual body weights were recorded prior dosing on day 0 and on days 7 and 14. At the end of the study the animals were killed and subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic carvities for examination of major organs. The appearance of any macroscopic abnormalities was recoded. No tissues were retained.
- Statistics:
- no data
- Preliminary study:
- There were no daeths or clinical signs of toxicity. Based on this information, a dose level of 2000 mg/kg body weight was selected for the main study.
- Sex:
- male/female
- Dose descriptor:
- LD50
- Effect level:
- > 2 000 mg/kg bw
- Mortality:
- There were no deaths
- Clinical signs:
- other: No signs of systemic toxicity were noted during the study.
- Gross pathology:
- No abnormalities were noted at necropsy.
- Other findings:
- no
- Interpretation of results:
- practically nontoxic
- Remarks:
- Migrated information at the tested dose Criteria used for interpretation of results: EU
- Conclusions:
- The acute oral median lethal dose of the test material was found to be greater than 2000 mg/kg body weight. No symbol and risk phrase are required according to EU labelling regulations.
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- no data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted according to state of the art methodology at that time; methods and results are presented in summary format; however information of purity of test item and number of test animal per group are missing .
- Principles of method if other than guideline:
- The study was conducted according to state of the art methodology at that time. No OECD guideline existed at that time.
- GLP compliance:
- not specified
- Test type:
- other: no data
- Limit test:
- no
- Species:
- rat
- Strain:
- other: ChR-CD
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: young adult
No further details are given. - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- no
- Doses:
- 2250 mg/kg
5000 mg/kg
7500 mg/kg
11000 mg/kg
17000 mg/kg
25000 mg/kg - No. of animals per sex per dose:
- no data
- Control animals:
- not specified
- Details on study design:
- Survivors were sacrificed 14 days later.
- Statistics:
- no data
- Preliminary study:
- no data
- Sex:
- male
- Dose descriptor:
- LD50
- Effect level:
- > 25 000 mg/kg bw
- Mortality:
- no data
- Clinical signs:
- other: Diarrhea (compound and/or metabolite excreted with feces) on day of dosing and wet perineal area on day after dosing at 5000 mg/kg and above.
- Gross pathology:
- no data
- Other findings:
- no
- Interpretation of results:
- practically nontoxic
- Remarks:
- Migrated information at the tested doses Criteria used for interpretation of results: EU
- Conclusions:
- Titanium dioxide, treated with 50/50 mono and bis butyl phosphate, has low'acute toxicity when administered orally to young adult ChR-CD male rats in single doses; its Approximate Lethal Dose (ALD) is greater than 25,000 mg/kg of body weight.
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: well documented publication with acceptable deviations. Rated as supporting information only, due to poorly described test material and occurence of mortalities due to false animal handling.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
- GLP compliance:
- no
- Test type:
- fixed dose procedure
- Limit test:
- yes
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Beijing Vitalriver Experimental Animal Technology Co. Ltd.
- Age at study initiation: not given
- Housing: Mice were housed in stainless steel cages by sex.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2
- Humidity (%): 60 +/- 10
- Photoperiod: 12 hours dark/light cycle
No further details are given. - Route of administration:
- oral: gavage
- Vehicle:
- other: Hydroxypropylmethyl cellulose (HPMC)
- Details on oral exposure:
- Animals were fasted over night. TiO2 suspension (in 0.5% HPMC) was given by a syringe via the gastrointestinal tract in a minute.
Food and water was provided 2h later. - Doses:
- 5000 mg/kg
- No. of animals per sex per dose:
- 10 females and 10 males per group
- Control animals:
- yes
- Details on study design:
- Symptoms and mortality were observed and recorded during the first 24 h. 14 days after dosage the animals were sacrificed and subjected to gross pathological examination. Additional examinations were performed but not further discussed here (see below).
- Statistics:
- Results were expressed as mean±standard deviation (S.D.). Multigroup comparisons of the means were carried out by one-way analysis of variance (ANOVA) test. Dunnett’s test was used to compare the differences between the experimental group and the control group. The statistical significance for all tests was set at p < 0.05.
- Preliminary study:
- no data
- Sex:
- male/female
- Dose descriptor:
- LD50
- Effect level:
- > 5 000 mg/kg bw
- Remarks on result:
- other: TiO2 155 nm
- Mortality:
- The reasons for the deaths were considered to be based on application mistakes (ruptured oesophagus) rather than test item induced:
2 female mice after 2 days
1 male mouse after 3 days - Clinical signs:
- other: No abnormal behaviour and signs were observed in the survivors.
- Gross pathology:
- No detailes given, except statement on not-substance induced mortalities due to inappropriate handling of test animals (rupture of oesophagus during gavage).
- Interpretation of results:
- not classified
- Remarks:
- Migrated information Criteria used for interpretation of results: EU
- Conclusions:
- Under the conditions of this study, the oral LD50 for Titanium dioxide (155 nm) was greater than 5000 mg/kg for male and female mice.
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 1989-05-19 to 1989-06-02
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study is comparable to guideline study. No certificate of GLP available, as the study was conducted before compulsory of GLP. Basic data of test item (purity, stability) are missing.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 401 (Acute Oral Toxicity)
- GLP compliance:
- yes
- Test type:
- standard acute method
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, U.K Limited, Manston Road, Margate, Kent
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 123-169 g
- Housing: The rats were housed by sex in polypropylene cages with mesh floors suspended over absorbent paper lined trays with a maximum of 5 animals per cage.
- Diet: The rats were fed Expanded Rat and Mouse Maintenance Diet, supplied by Special Diets Services, 1 Stepfield, Witham, Essex, CM8 3AD, but were deprived of food for 16-18 h before dosing and for 3-4 h post dosing.
- Water: ad libitum
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22
- Humidity (%): 44
- Photoperiod: 12 hours dark/light - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- On the day of dosing, NP 89/95 was freshly prepared in distilled water at a concentration of 500 mg/ml.
- Doses:
- Dose level: 5000 mg/kg
Dose volume: 10 ml/kg - No. of animals per sex per dose:
- 6 males and 5 females
- Control animals:
- not specified
- Details on study design:
- The rats were observed frequently on the day of dosing and once daily for 14 days following dosing. They were weighed immediately prior to dosing, 7 days after dosing and at sacrifice at the end of the 14 day observation period. At the end of the observation period and sacrifice by carbon dioxide
asphyxiation, each animal was subjected to a gross post mortem examination. - Statistics:
- no data
- Preliminary study:
- no data
- Sex:
- male/female
- Dose descriptor:
- LD50
- Effect level:
- > 5 000 mg/kg bw
- Mortality:
- There was no mortality.
- Clinical signs:
- other: Clinical signs, noted 0.5 hours to 7 days after dosing, were confined to piloerection.
- Gross pathology:
- No gross post mortem abnormalities were observed.
- Other findings:
- no
- Interpretation of results:
- practically nontoxic
- Remarks:
- Migrated information at the tested dose Criteria used for interpretation of results: EU
- Conclusions:
- There were no deaths following a single oral dose of NP 89/96 at a dose level of 5000 mg.kg'1, to a group of 5 male and 5 female rats.
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 2006-05-10 to 2006-08-01
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study; no GLP compliance statement.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.1100 (Acute Oral Toxicity)
- GLP compliance:
- no
- Test type:
- up-and-down procedure
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: 9-11 weeks
- Fasting period before study: 16-18 hours
- Housing: All animals were housed singly in stainless steel, wire-mesh cages suspended above cage boards.
- Diet: ad libitum; PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002
- Water: ad libitum
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26
- Humidity (%): 30-70
- Photoperiod: 12-hour light/dark cycle
No further details are given. - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- Individual dose volumes were calculated using the fasted body weights obtained prior to dosing. The rats were dosed at a volume of 10 ml per kg of body weight. The dosing suspensions were stirred prior to and throughout the dosing procedure. A single oral dose of H-27416, suspended in deionised water, was administered by oral gavage to one fasted fasted female rat each.
- Doses:
- 175, 550 and 1750 mg/kg and three fasted female rats at a dose of 5000 mg/kg
- No. of animals per sex per dose:
- 6 rats: 1 or 3 rats per dose
- Control animals:
- not specified
- Details on study design:
- The rats were dosed one at a time at a minimum of 48-hour intervals.
Observations for mortality and signs of illness, injury, or abnormal behavior were made daily throughout the study. The rats were observed for clinical signs at the beginning of fasting, just before dosing (test day 0), once during the first 30 minutes after dosing and 2 more times on the day of dosing, and once each day thereafter. The rats were weighed on test days –1, 0, 7, and 14. On test day 14, the surviving rats were euthanized and necropsied to detect grossly observable evidence of organ or tissue damage or dysfunction. The rats were anesthetised by carbon dioxide and euthanised by exsanguination. - Statistics:
- A software package (A0T425StatPgm)a was used to determine the dose progression and to calculate the LD50.
- Preliminary study:
- no data
- Dose descriptor:
- LD50
- Effect level:
- > 5 000 mg/kg bw
- Mortality:
- No deaths occurred.
- Clinical signs:
- other: The rat dosed at 1750 mg/kg and the three rats dosed at 5000 mg/kg exhibited grey colored feces beginning the day after dosing and up to 5 days after dosing.
- Gross pathology:
- No gross lesions were present in the rats at necropsy.
- Other findings:
- no
- Interpretation of results:
- practically nontoxic
- Remarks:
- Migrated information for the tested doses Criteria used for interpretation of results: EU
- Conclusions:
- Under the conditions of this study, the oral LD50 for titanium dioxide (sample: H-27416) was greater than 5000 mg/kg for female rats.
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 1994-08-22 to 1994-10-06
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Comparable to guideline study with acceptable restrictions: - the number of test animal in a dose group is not in compliance with the guideline, however none of the 3 animals administered a dose of ≥ 5000 mg/kg died, therefore according to the criteria specified by Directive 67/548/EC and subsequent regulations the test item is not toxic and therefore no classification is required.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
- Deviations:
- yes
- Remarks:
- the number of test animal in a dose group is not in compliance with the guideline
- Principles of method if other than guideline:
- Comparable to guideline study with acceptable restrictions:
- the number of test animal in a dose group is not in compliance with the guideline, however none of the 3 animals administered a dose of ≥ 5000 mg/kg died, therefore according to the criteria specified by Directive 67/548/EC and subsequent regulations the test item is not toxic and therefore no classification is required. - GLP compliance:
- no
- Test type:
- other: not applicable
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:DC BR
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Raleigh, North Carolina
- Age at study initiation: 7 weeks
- Housing: Rats were housed singly in suspended, stainless steel, wire-mesh cages.
- Diet: ad libitum; Purina Certified Rodent Chow #5002
- Water: ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 2
- Humidity (%): 50 +/- 10
- Photoperiod: 12 hours dark/light cycle
No further details are given. - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- The test substance was suspended in deionised water and administered to 1 rat per dose rate by intragastric intubation. In the absence of visible evidence to the contray, the test substance was assumed to be stable under the conditions of administration.
- Doses:
- Dose rates administered ranged from 2300 to 11000 mg/kg of body weight in increments of approximately 50%. Additionally, 1 rats was dosed at 670 mg/kg.
- No. of animals per sex per dose:
- 1 rat per dose; 6 rats
- Control animals:
- not specified
- Details on study design:
- The dosing day was test day 1; postexposure day 14 was test day 15. Following administration of the test substance, rats were observed for clinical signs of toxicity. Surviving rats were weighed and observed daily until signs of toxicity subsided, and then at least 3 times per week throughout the 14 or 15-day observation period. Observations for mortality were made daily throughout the study. Pathological examinations of the test animals were not performed.
- Statistics:
- no data
- Preliminary study:
- no data
- Sex:
- male
- Dose descriptor:
- LD50
- Effect level:
- > 11 000 mg/kg bw
- Mortality:
- No deaths occurred during the study.
- Clinical signs:
- other: No clinical signs of toxicity were observed in the treated rats.
- Gross pathology:
- no
- Other findings:
- no
- Interpretation of results:
- practically nontoxic
- Remarks:
- Migrated information Criteria used for interpretation of results: EU
- Conclusions:
- Under the conditions of the study, the ALD for H-20762 was greater than 11000 mg/kg body weight. This substance is considered to be very low in toxicity (ALD greater than 5000 mg/kg) when administered as a single oral dose to male rats.
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: well documented publication with acceptable deviations. Rated as supporting information only, due to poorly described test material and occurence of mortalities due to false animal handling.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
- GLP compliance:
- no
- Test type:
- fixed dose procedure
- Limit test:
- yes
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Beijing Vitalriver Experimental Animal Technology Co. Ltd.
- Age at study initiation: not given
- Housing: Mice were housed in stainless steel cages by sex.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2
- Humidity (%): 60 +/- 10
- Photoperiod: 12 hours dark/light cycle
No further details are given. - Route of administration:
- oral: gavage
- Vehicle:
- other: Hydroxypropylmethyl cellulose (HPMC)
- Details on oral exposure:
- Animals were fasted over night. TiO2 suspension (in 0.5% HPMC) was given by a syringe via the gastrointestinal tract in a minute.
Food and water was provided 2h later. - Doses:
- 5000 mg/kg
- No. of animals per sex per dose:
- 10 females and 10 males per group
- Control animals:
- yes
- Details on study design:
- Symptoms and mortality were observed and recorded during the first 24 h. 14 days after dosage the animals were sacrificed and subjected to gross pathological examination. Additional examinations were performed but not further discussed here (see below).
- Statistics:
- Results were expressed as mean±standard deviation (S.D.). Multigroup comparisons of the means were carried out by one-way analysis of variance (ANOVA) test. Dunnett’s test was used to compare the differences between the experimental groups and the control group. The statistical significance for all tests was set at p < 0.05.
- Preliminary study:
- no data
- Sex:
- male/female
- Dose descriptor:
- LD50
- Effect level:
- > 5 000 mg/kg bw
- Remarks on result:
- other: TiO2 25 nm
- Sex:
- male/female
- Dose descriptor:
- LD50
- Effect level:
- > 5 000 mg/kg bw
- Remarks on result:
- other: TiO2 80 nm
- Mortality:
- The reasons for the deaths were considered to be based on application mistakes (ruptured oesophagus) rather than test item induced:
2 female mice (25 nm group) after 2 days
1 female mouse (80 nm group) after 2 days
1 female mouse (25 nm group) after 3 days - Clinical signs:
- other: No abnormal behaviour and signs were observed in the survivors.
- Gross pathology:
- No detailes given, except statement on not-substance induced mortalities due to inappropriate handling of test animals (rupture of oesophagus during gavage).
- Interpretation of results:
- not classified
- Remarks:
- Criteria used for interpretation of results: EU
- Conclusions:
- Under the conditions of this study, the oral LD50 for Titanium dioxide (25 nm and 80 nm) was greater than 5000 mg/kg for male and female mice.
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- One key study available (according to OECD 420, under GLP) which is reliable with only minor restrictions (RL=2). The overall quality of the database is therefore high.
Acute toxicity: via inhalation route
Link to relevant study records
- Endpoint:
- acute toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- no data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline study with acceptable restrictions: - GLP is not compulsory at the time of conduct - Purity and stability of test items are missing
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 403 (Acute Inhalation Toxicity)
- GLP compliance:
- no
- Test type:
- fixed concentration procedure
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, England
- Weight at study initiation: 104-127 g
- Housing: The rats were housed in a semi-barrier maintained animal room. Rats were housed 1 or 2 males or females per cage in suspended polypropylene cages with detachable stainless steel tops and bottoms. All cages were suspended over trays containing absorbent paper.
- Diet: ad libitum, except during the 4 hours exposure period; Rat and House (Modified) No. 1 Diet SQC Expanded
- Water: ad libitum, except during the 4 hours exposure period
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2
- Humidity (%): 55
- Photoperiod. 12 hours dark/light cycle
No further details are given. - Route of administration:
- inhalation
- Type of inhalation exposure:
- nose only
- Vehicle:
- other: air
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The aluminium exposure chamber was cylindrical in cross section and had a volume of approximately 41.5 litres.
- System of generating particulates/aerosols: The test atmospheres were generated using an Aerostyle dust generator. Filtered, oil-free compressed air for the production of the test aerosol was supplied by Hydrovane compressors.
- Method of particle size determination: The particle size distribution of the dispersed material inside the exposure chamber was estimated twice during the exposure period using a Marple (Model 296) Cascade Impactor.
- Temperature, humidity, pressure in air chamber: During the exposure periods the temperature within the exposure chamber was measured by a mercury thermometer located at the animals' breathing zone whilst the relative humidity was monitored using wet/dry bulb mercury thermometers. The chamber temperature and relative humidity were measured at 30 min intervals throughout the exposure periods and ranged from 25-26°C and 19-35% respectively for temperature and humidity.
TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Particle size distribution measurements revealed that the percentage of particles <3.5 µm was 20% by weight for NP 89/117
- MMAD: 7.0 µm for NP 89/117
No further details are given. - Analytical verification of test atmosphere concentrations:
- yes
- Remarks:
- Chamber concentrations were measured gravimetrically at regular intervals during the exposure periods.
- Duration of exposure:
- 4 h
- Concentrations:
- measured:
NP 89/117: 5.09 mg/l (MMD=7µm) - No. of animals per sex per dose:
- groups of 5 males and 5 females
- Control animals:
- not specified
- Details on study design:
- During exposure the animals were observed at regular intervals for signs of any adverse reactions to treatment. On completion of the 4 hours exposure period, the animals were removed from the chamber, unloaded from the restraint tube, returned to their cages in the animal holding room and observed for clinical signs.
All the rats were observed for clinical signs at frequent intervals throughout the exposure period, for the first 1-2 hours post dosing and thereafter at least once daily during the subsequent 14 day observation period. The onset, intensity and duration of any signs observed were recorded.
All the rats were weighed immediately before dosing and on Days 2, 3, 4, 7, 10 and 14 post exposure.
At the end of the 14 day observation period all the animals were sacrificed and subjected to a macroscopic post mortem examination. - Statistics:
- no data
- Preliminary study:
- no data
- Sex:
- male
- Dose descriptor:
- LC50
- Effect level:
- 5.09 mg/L air
- Exp. duration:
- 4 h
- Remarks on result:
- other: NP 89/117
- Mortality:
- There were no mortalities.
- Clinical signs:
- other: No adverse clinical signs were observed as a result of exposure to NP 89/117
- Body weight:
- No adverse effect on body weight gain was observed.
- Gross pathology:
- Gross pathological examination revealed pale lungs for 3/5 male and 1/5 female animals exposed to NP 89/117.
- Other findings:
- The lung body weight ratios for all the animals were considered to be within normal limits.
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The Titanium Dioxide Powder NP 89/117 was considered to be non-toxic to rats by the inhalation route at measured atmospheric concentrations of 5.09 mg/L air.
- Executive summary:
McDonald, P. & Oshodi, R.O. (1989) exposed male and female rats to ultrafine titanium dioxide according to OECD guideline 403. In a limit test, the rats were exposed nose only with 5.09 mg/L for 4 hours. Each group consisted of 5 female and 5 male rats. Gross pathological examination revealed pale lungs in 3/5 male and 1/5 female animals in the ultrafine group. However, no test item related toxicity, no body weight loss occurred after dosing, and no clinical signs were present during the conduct of the study. Hence, titanium dioxide powder was considered to be non-toxic to rats by the inhalation route at measured atmospheric concentration of 5.09 mg/L.
- Endpoint:
- acute toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- no data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted according to state of the art methodology at that time; methods and results are presented in summary format, hwoever the study is comparable to guideline study with acceptable restrictions: - lack of necropsy
- Principles of method if other than guideline:
- The study was conducted according to state of the art methodology at that time. No OECD guideline existed at that time.
- GLP compliance:
- not specified
- Test type:
- other: no data
- Limit test:
- no
- Species:
- rat
- Strain:
- other: ChR-CD
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 254-287 g
- Diet: ad libitum
- Water: ad libitum
No further details are given. - Route of administration:
- inhalation
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: air
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- System of generating particulates/aerosols: Particles of titanium dioxide were introduced into a 30-litre exposure chamber by passing houseline air (approx. 20 l/min) through a cyclone-head type dust generator taht contained the test material.
- Method of particle size determination: A brinks Cascade Impactor was used to determine the mass median diameter of generated particles.
TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.55 µm and 1.70
No further details are given. - Analytical verification of test atmosphere concentrations:
- yes
- Remarks:
- The concentration of the test material in the exposure chamber was determined gravimetrically.
- Duration of exposure:
- 4 h
- Concentrations:
- 4.99 mg/l and 6.82 mg/l
- No. of animals per sex per dose:
- 6 rats
- Control animals:
- not specified
- Details on study design:
- Following exposure, the test rats were placed in a recovery area and observed and weighed daily for 14 days.
- Statistics:
- no data
- Sex:
- male
- Dose descriptor:
- LC50
- Effect level:
- > 6.82 mg/L air
- Exp. duration:
- 4 h
- Mortality:
- No mortality was observed.
- Clinical signs:
- other: Immediately following exposure, the rats exposed at the 6.82 mg/l concentration level displayed irregular respiration, gasping, lethargy, red eye discharge and nasal discharge. No remarkable clinical signs were noted at the 4.99 mg/l exposure level.
- Body weight:
- Both test groups showed slight weight loss between days 1-2 of recovery with subsequent normal weight gain from days 3 to end of recovery period.
- Gross pathology:
- no data
- Other findings:
- no
- Interpretation of results:
- practically nontoxic
- Remarks:
- Migrated information at the tested exposure levels Criteria used for interpretation of results: EU
- Conclusions:
- The approximate lethal concentration (LC50) of titanium dioxide in male rats exposed head-only for 4 hours, is greater than 6.82 mg/L (the highest test concentration practical). According to the criteria specified by Directive 67/548/EC and subsequent regulations the test item requires no classification.
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- Two key studies available which are reliable with only minor restrictions (RL=2). The overall quality of the database is therefore high.
Acute toxicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Acute oral toxicity
Acute oral toxicity studies with pigment-grade titanium dioxide
Two acute oral toxicity studies with pigment-grade titanium dioxide in rats are available, conducted according to OECD guidelines 401 or according to state of the art methodology at that time.
In the study by Sanders, A. (1996) treated (not further specified) titanium dioxide (pigment grade) was used to expose rats at 2,000 mg/kg bw by gavage. Each group consisted of 5 male and 5 female rats. During the conduct of the study no test item related toxicity, no body weight loss occurred after dosing, and no gross lesions were present in the rats at necropsy. The study reports an LD50 > 2,000 mg/kg bw in rats.
In the other study (Carroll, K.S., 1971), titanium dioxide treated with 50/50 mono and bis butyl phosphate was used to expose male rats. Rats were dosed at 2,250 - 25,000 mg/kg bw by single gavage. Clinical signs on the day of dosing were limited to diarrhoea. No substance-related toxicity was observed, thus indicating an oral LD50 in excess of 25,000 mg/kg bw in rats.
Additionally, in a study by Wang J. et al. (2007), male and female mice were treated in a limit test with fine (155 nm) titanium dioxide at a dose of 5,000 mg/kg bw via gavage. Control and treatment group consisted of 10 male and 10 female mice. Two female mice died after 2 days and one male mouse after 3 days due to inappropriate handling of test animals (rupture of oesophagus during gavage). However, during the conduct of the study no test item related toxicity, no body weight loss occurred after dosing, and no gross lesions were present in the mice at necropsy. Hence, the study reports an LD50 > 5,000 mg/kg bw in mice.
Acute oral toxicity studies with ultrafine titanium dioxide
Finlay et al. (2006) exposed female rats to ultrafine titanium dioxide (uncoated, 100% purity: 79% rutile, 21% anatase). Rats were dosed with 175, 550, 1,750 and 5,000 mg/kg bw via gavage. Each group consisted of 1 or 3 female rats. Clinical signs observed at the rat dosed at 1,750 mg/kg and the three rats dosed at 5,000 mg/kg were limited to grey coloured faeces beginning the day after dosing and up to 5 days after dosing. No substance related toxicity was. In this study, a LD50 > 5,000 mg/kg bw in rats was derived.
In another study by Cuthbert and Jackson (1989), male and female rats were exposed to ultrafine titanium dioxide (uncoated). Rats were dosed with 5,000 mg/kg bw by single gavage. Each group consisted of 6 male and 5 female rats. Clinical signs, noted 0.5 hours to 7 days after dosing, were limited to piloerection. No substance related toxicity has been observed, thus a LD50 > 5,000 mg/kg bw in rats was derived.
Sarver (1994) treated male rats with ultrafine titanium dioxide (uncoated). Rats were dosed at 2,300 up to 11,000 mg/kg bw by single gavage. Each group consisted of 1 male rat. No substance related toxicity was, thus a LD50 > 11,000 mg/kg bw in rats was derived.
In the study by Wang J. et al. (2007), male and female mice were treated in a limit test with nano-sized (80 nm and 25 nm) titanium dioxide at a dose of 5,000 mg/kg bw via gavage. Each group consisted of 10 male and 10 female mice. Two female mice of the 25 nm group died after 2 days and one female mouse in the 80 nm and one female mouse in the 25 nm group died after 2 days and 3 days, respectively. However, the recoded mortalities were not test-item related but due to inappropriate handling of test animals (rupture of oesophagus during gavage). During the conduct of the study no test item related toxicity, no body weight loss occurred after dosing, and no gross lesions were present in the mice at necropsy. Hence, the study reports an LD50 > 5,000 mg/kg bw in mice.
Disregarded information on ultrafine titanium dioxide likewise indicates a lack of acute oral toxicity: the study by Spanjers and Til (1979) performed with 10 rats (male/female) at a dose of 10,000 mg/kg bw indicate that the oral LD50 is in excess of 10,000 mg/kg bw in rats.
Conclusion
The available acute oral toxicity studies showed no mortality or other signs of toxicity after single oral administration of pigment-grade or ultrafine titanium dioxide up to doses of 25,000 mg/kg bw in rats. It is therefore concluded in a weight of evidence approach, taking into account all above information, that the LD50 for titanium dioxide is >>5,000 mg/kg bw.
Acute inhalation toxicity
Acute inhalation toxicity studies with pigment-grade titanium dioxide
Hall, G.T. (1979) treated male rats to rutile titanium dioxide (purity: 95.3% with 3.7% diantimony trioxide and 1% dialuminium trioxide micronised with 0.3% triethanolamine). Rats were exposed head only with 4.99 mg/L (MMAD 1.55 µm) and 6.82 mg/L (MMAD 1.70 µm) for 4 hours. Each group consisted of 6 male rats and was observed for a further 14 days. Immediately following exposure, the rats exposed at the 6.82 mg/L concentration level displayed irregular respiration, gasping, lethargy, red eye discharge and nasal discharge. No remarkable clinical signs were noted at the 4.99 mg/L exposure level. However, no test item related toxicity or body weight loss occurred during the conduct of the study. Hence, the study reports a LC50 > 6.82 mg/L (MMAD 1.55 – 1.70 µm).
McDonald, P. & Oshodi, R.O. (1989) exposed male and female rats to coated fine titanium dioxide according to OECD guideline 403. In a limit test, the rats were exposed nose only with 3.43 mg/L for 4 hours. Each group consisted of 5 female and 5 male rats. Gross pathological examination revealed mottled lungs for 2/5 male and 3/5 female animals in the coated fine group. However, no test item related toxicity, no body weight loss occurred after dosing, and no clinical signs were present during the conduct of the study. Hence, titanium dioxide powder was considered to be non-toxic to rats by the inhalation route at measured atmospheric concentrations of 3.43 mg/L.
Hall, G.T. (1979) treated male rats to rutile titanium dioxide (purity: 97% with 2% diantimony trioxide and 1% dialuminium trioxide). Rats were exposed head only with 1.37, 1.94 and 3.56 mg/L (TWA) or with1.63, 1.87 and 2.28 mg/L (TWA) for 4 hours. The mass median diameters were in the range of 1.85 – 2.8 µm and 1.5 – 1.75, respectively. Each group consisted of 6 male rats and was observed for further 14 days. The test rats displayed chewing and blinking motions and sporadic cases of eye discharge. Irregular respiration and lethargy were noticed in a few rats exposed to 1.87, 2.28 and 3.56 mg/L. However, no test item related toxicity or body weight loss occurred during the conduct of the studies. Hence, the studies report a LC50 > 3.56 mg/L (MMAD 1.85 – 2.80 µm) and LC50 > 2.28 mg/L (MMAD 1.5 – 1.75 µm), respectively.
Karlsson (1986) conducted an inhalation study in female Sprague-Dawley rats. Animals were exposed for 10 min to concentrations of 2.5, 5.0 and 7.5 g TiO2-HC. However, for an evaluation of the acute inhalation toxicity of test item, the selected concentrations were too low and the exposure duration was too short (verified test concentrations of Ti: 1.2, 2.0 and 2.2 mg/L). A constant concentration of test item atmosphere could not be ensured over the exposure period. The animals were exposed to a substance mixture, thus the study does not provide meaningful data on the acute inhalation toxicity of titanium dioxide alone. Consequently, the study is considered not reliable for hazard assessment purposes.
Rylander (1979) investigated the number of macrophages and leukocytes in BALF 24-hours after inhalation exposure of titanium dioxide in guinea-pigs. No mortality occurred 24-hr after inhalation exposure at 0.9 mg/m³. The study design and the reporting exhibits deficiencies which do not allow an independent assessment of the study; in brief: strain, sex, age and body weight of animals not reported, clinical status not reported, post exposure observation period too short for LC50 determination and necropsy was not performed. The study was disregarded for hazard and risk assessment purposes.
Acute inhalation toxicity studies with ultrafine titanium dioxide
McDonald, P. & Oshodi, R.O. (1989) exposed male and female rats to ultrafine titanium dioxide according to OECD guideline 403. In a limit test, the rats were exposed nose only with 5.09 mg/L for 4 hours. Each group consisted of 5 female and 5 male rats. Gross pathological examination revealed pale lungs in 3/5 male and 1/5 female animals in the ultrafine group. However, no test item related toxicity, no body weight loss occurred after dosing, and no clinical signs were present during the conduct of the study. Hence, titanium dioxide powder was considered to be non-toxic to rats by the inhalation route at measured atmospheric concentration of 5.09 mg/L.
Oyabu (2015) exposed rats for 6 hours at concentrations of 4 mg/m³ via whole body or nose only. The aim of this study was to investigate differences for the two exposure conditions. No mortality occurred, and the histopathological examination showed no infiltrations of inflammatory cells in the alveolar space and interstitium, fibrosis or tumorigenesis in any of the animals. Macrophage-engulfed pigment-like components both in whole-body and nose-only exposures were the only observations in the treated groups. Due to the unsuitable study design with the following major restrictions, this study will not be used for hazard and risk assessment purposes but merely as supplementary mechanistic information; in brief: only males were used, details on animal housing conditions and animal randomization not included, the test item was not sufficiently characterised. Animals were sacrificed immediately after the exposure period of 6 hrs. No observation period of 14 days was included. No clinical observations during exposure were stated and the cage-side observation was not conducted. No gross necropsy was performed.
In the study by Noël et al. (2012), male CDF (F344)/CrlBR rats were exposed for 6 h via nose-only inhalation with 2 and 7 mg/m³ ultrafine TiO2. Aerosols were generated using two different systems leading to nano-aerosols marked by large particle agglomerates (LA, >100 nm) or small particle agglomerates (SA, <100 nm). Animals were sacrificed and bronchoalveolar lavage (BAL) was performed 16 h after treatment. BAL fluid was analysed for differential cell counts (lymphocytes, neutrophils, and macrophages), markers of inflammation, oxidative stress, 8-Isoprostane, and Heme-oxygenase 1 and cytotoxicity. According to the authors, exposure to 2 mg/m³ of small agglomerate or large agglomerate TiO2 nano-aerosols did not lead to significant changes of the parameters tested, except an increased neutrophil level in rats exposed to TiO2 nano-aerosol with large agglomerates at a concentration of 7 mg/m³. The authors claimed that the different agglomeration states showed distinct effects after exposure. Large TiO2 agglomerates were massively phagocytised by macrophages and showed inflammatory signs like elevated neutrophil and cytokine MCP-1 levels, after exposure. In contrast, exposure to small agglomerates did not lead to accumulation of particle-laden macrophages and resulted in elevated levels of oxidative stress (8-Isoprostane) and cytotoxicity (LDH). The results of the study are difficult to interpret due to shortcomings in the study design, which was not in accordance with any accepted guideline. The test material was insufficiently characterised. Due to an absence of a clear designation, purity or impurity information, it remains unclear whether the test item was in fact of industrial origin and therefore of relevance for the hazard and risk assessment of titanium dioxide. Further, the description of the BAL procedure contains contradictory details. MMAD and GSD of the aerosols are not specified, and details of animal husbandry are missing. Observed clinical signs or mortality, performance and results of necropsy not reported. Results were only presented as normalized values without control data. Based on the above-mentioned shortcomings, the reference is considered not reliable and disregarded for hazard assessment purposes.
In the study by Noël et al. (2013), male CDF (F344)/CrlBR rats were exposed for 6 h via nose-only inhalation to three different TiO2 ultrafine particle types (5 nm, 10-30 nm, and 50 nm) at a concentration of 20 mg/m³. Aerosols were generated using two different systems leading to nano-aerosols marked by large particle agglomerates (LA, >100 nm) or small particle agglomerates (SA, <100 nm). Animals were sacrificed 16 h after treatment. Afterwards, BAL fluid analysis and lung histopathological examinations were performed. BAL fluid was analysed for differential cell counts (lymphocytes, neutrophils, and macrophages), inflammation levels (expression of 29 cytokines), oxidative stress (8-isoprostane level), and cytotoxicity (lactate dehydrogenase activity). According to the authors, exposure with LA aerosols resulted in an acute inflammatory response, characterized by a significant neutrophil number increase. In contrast, treatment with SA aerosols resulted in significantly higher levels of oxidative stress and cytotoxicity. However, cytotoxicity was only significantly higher in SA aerosol based on 5 nm TiO2 particles. In general, the response was strongest for 10-30 nm particles independent of the agglomerate size.
The results of the study are difficult to interpret due to shortcomings in study design, which is not in accordance with any accepted guideline. The test materials are insufficiently characterised. Details on purity or impurity are missing. The method section lacks several details. MMAD and GSD of the TiO2 nano-aerosols are not specified. Air changes per hour are not specified. Details on animal husbandry are missing. Body weights at study initiation and information on test group randomisation are not specified. BAL procedure is not described sufficiently. Further, the description of the BAL procedure contains contradictory details. MMAD and GSD of the aerosols are not specified, details on animal husbandry are missing. Observed clinical signs or mortality, performance and results of necropsy not reported. Results were only presented as normalized values without control data. Based on the above-mentioned shortcomings, the reference is considered not reliable and disregarded for hazard assessment purposes. Statistical test used are not described sufficiently, it was not stated which type of ANOVA was performed and for which analysis. Result section shows some deficiencies. The authors do not state on observed clinical signs or mortality. Performance and results of gross necropsy are not specified. Results are not presented as individual rat values. Based on the above-mentioned shortcomings the reference is considered not reliable.
Summary entry- acute inhalation
No conclusions can be drawn from the publications summarised in this entry due to lack of quality, reliability and adequacy of the experimental data for the fulfilment of data requirements under REACH. The reference contained in this entry represent in vivo experiments with investigations of acute inhalation toxicity of very limited value for risk assessment purposes. The references do not fulfil the criteria for quality, reliability and adequacy of experimental data of the data requirements under REACH and hazard assessment purposes (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annexes VII-X). The information contained therein was included for information purposes only:
Besov, A. S. et al.(2010)
The test conditions (test animal strain, housing, experimental setup) are insufficiently discribed and necropsy was not executed at the end of the study, only animal behavior was observed during the study. Furthermore, the effect of highly toxic DFP vapors in mixture with TiO2 aerosol administration is not suitable for any hazard assessment of the test substance alone.
LeBlanc, A.J. et al. (2009):
The test conditions (test animal strain, housing, experimental setup) are insufficiently described, necropsy was not executed and animal behavior was not observed during the study. Further, the authors used just one concentration for their experiments (at least three are recommended by the OECD). Moreover, the authors do not specify indiviual rat values for any experiment.
Nurkiewicz, T.R. et al.(2011):
The test conditions (housing, test group randomization, environmental conditions) are insufficiently described, clinical signs and behavior during treatment are not stated, and necropsy was not executed at the end of the study. MMAD is not specified.
Conclusion
In the acute inhalation toxicity studies with titanium dioxide dust (pigment grade and ultrafine), rats were head and nose only exposed for 4 hours with up to 6.82 mg/L air. During the conduct of the studies no mortalities occurred. Therefore, the LC50 inhalation, rat was derived to be > 6.82 mg/L air.
Acute dermal toxicity
There are no reliable reports whatsoever on acute dermal toxicity in the public domain. However, the conduct of acute dermal toxicity testing is not considered to be required since inhalation of the substance is considered the most relevant route of human exposure, and physicochemical properties and dermal absorption data of the substance do not suggest a significant rate of absorption through the skin (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006). In addition, the long-term dermal cosmetic use of titanium dioxide in sunscreens has been without any reported adverse effects.
Acute toxicity – other routes
Xu et al. (2013) evaluated the acute toxicity of TiO2 after a single intravenous injection of TiO2 suspensions in male and female ICR mice (4M/4F per dose group) at 0, 140, 300, 645, and 1387 mg/kg bw. 14 days after the injections, behaviour, mortality and organ weights were recorded and blood biochemical and haematology analysis as well as histopathology examination was performed. Mortality of 2 males and 4 females in the highest treatment group was observed. Organ weights of spleen increased, while organ weights of liver and kidney decreased in TiO2 NP treated animals. Bilirubin levels decreased and WBC increased in a dose dependent manner. Histopathology revealed different degrees of damage in the brain, lung, spleen, liver and kidneys. The test material was however insufficiently characterised. Due to an absence of a clear designation, purity or impurity information, it remains unclear whether the test item was in fact of industrial origin and therefore of relevance for the hazard and risk assessment of titanium dioxide. This study is not in accordance with any OECD acute toxicity guideline. The initial age of the animals and the body weight at the beginning of the study are not stated. The test substance was administered via intravenous injection which is not considered a physiological route of administration. The injection volume was not specified and a concentration determination of the TiO2 NP suspension prior administration was not performed. Additionally, the body weights throughout the study were not recorded. Based on the above listed shortcomings, the study was considered not reliable and was therefore disregarded.
Danielsen, P.H. et al.(2020) investigated on pulmonary inflammation in female C57BL/6jBomtac after single intratracheal instillations with four different titanium dioxide nanoparticles types. The titanium dioxide nanoparticles, TiO2 NM-1 (MKN-A015), TiO2 NM-2 (MKN-A100), TiO2 tubes (self-synthesised), and TiO2 cubes (self-synthesised), were administered once at total dose levels of 18, 54, and 162 µg per mice. Lung tissue and BALF cells were obtained after 1, 3, 28, 90, 180 days post-exposure. Vehicle control groups were run concurrently. The quartz (DQ12) was included as benchmark material. The pulmonary inflammation was evaluated via the analysis of the cell composition of BALF and histopathological examination of lung tissue. Moreover, the authors investigated on the particle distribution in the lung via different microscopical techniques. Further, the pulmonary and hepatic acute phase response was assessed via gene expression analysis of Saa3 and Saa1, respectively. In addition, the authors investigated on DNA damage in BALF, lung, and liver cells (c.f. section 7.6.2.). According to the authors, single intratracheal instillation of resulted only in a transient neutrophil influx except for the exposure to TiO2 tube. The administration of TiO2 tube resulted in statistically significantly increased neutrophil, macrophages, lymphocytes, and total cells levels at post-exposure day 28. Moreover, statistically significantly levels of neutrophils and lymphocytes were also observed at post-exposure day 180. In general, the inflammatory response was more marked after TiO2 tube exposure. This finding was substantiated by histopathological examinations of the lungs showing significant changes after TiO2 tube exposure and only moderate inflammatory changes for the other TiO2 NP types. Microscopical analyses of the particle distribution revealed that the particles were observed in phagosomal vesicles of macrophages and in the alveolar lumen. All four TiO2 NMs were detected in lung tissue up to 180 days post-exposure. The publication shows several reporting and methodological deficiencies. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. The administration via intratracheal instillation is a non-physiological route of exposure and considered to be not relevant. The investigated mechanistic parameters (e.g. bronchoalveolar lavage (BAL) fluid analyses and gene expression analysis have no direct value for fulfilling data requirements under the REACH regulation. Differential cell counts were only reported as absolute counts; however, information on proportions are not given. The authors provided no information on systemic effects. The characterisation of the test material lacks some details, e.g., purity and potential surface modifications. The test animals and the test animal housing conditions are not sufficiently described. Historical control data is not included. The vehicle controls were combined for each post- exposure day per dose group. Indicators for lung damage were not evaluated, e.g., total protein level or LDH activity in BALF. Based on the above-mentioned shortcomings the reference is considered not reliable.
Summary entries - instillation
Several mechanistic studies investigated the inflammatory response of ultrafine titanium dioxide following single administration via oropharyngeal aspiration, nasal and intratracheal instillation, whole-body and nose-only inhalation. All references do not fulfil the criteria for quality, reliability and adequacy of experimental data for data requirements under REACH and for hazard assessment purposes. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Where applicable, a number of these studies were considered in the assessment of differences in effects elicited in the respiratory tract of surface modified and non-surface modified titanium dioxide. A comprehensive discussion is provided in Appendix XYZ to this CSR. The following references are reported as disregarded study records in summary entries, presenting some essential details for information purposes only:
Oberdörster, G. et al. (1992): Investigated mechanistic parameters, such as translocation of particles after intratracheal instillation of the test substance.
Renwick, L. C. et al.(2004): Investigated mechanistic parameters, such as phagocytosis and chemotaxis measurement of macrophages after intratracheal instillation of the test substance.
Warheit, D. B. et al.(2007): Investigated mechanistic parameters, such as bronchoalveolar lavage (BAL) fluid inflammatory markers and cell proliferation after intratracheal instillation of the test substance.
Ahn, M.-H. et al. (2005): Investigated mechanistic parameters, such as bronchoalveolar lavage (BAL) fluid values and gene expression measurements after intratracheal instillation of the test substance.
Mizuno, K (2011): The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. The raw data and referred tables are not included in the publication.
Hashizume, N. et al. (2016): Investigated mechanistic parameters, such as bronchoalveolar lavage (BAL) fluid inflammatory markers and cell proliferation after intratracheal instillation of the test materials.
Rahman, L. et al. (2017): The methodical setup is not adequately designed for risk assessment purposes of the test substance. Aeroxide TiO2 P25 was suspended in water; P25 has been shown to have a strong acidic (pH 3.28) effect. Intratracheal instillation of a strong acidic solution could lead to false positive findings. Clinical observations and gross necropsy were not reported. Body weight or bodyweight changes were not stated. Results are not presented as individual values or in summarised form.
Gustafsson, A. et al. (2011): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid immune response marker analysis and analysis of cytokine concentration in the serum after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance.
Okada, T. et al. (2016): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analysis after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. The authors do not state on potential pH effects of the test item which was suspended in drinking water. However, it was reported for P25 TiO2 nanoparticles to show strong, acidic pH-effects (pH 3.28) in deionized water (Warheit et al. 2007). Discrimination between the origins of observed effects is even more impeded by the lack of cytotoxicity measurements.
Saber, A.T. et al.(2012): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. Only a single dose was administered, which impedes dose-response relationship analysis. The authors performed only an in vitro assay as positive control. Historical data are missing.
Saber, A.T. et al. (2012): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. The authors performed only an in vitro assay as positive control. Historical data are missing.
Warheit, D.B. et al. (2005): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. Instillation volume is not specified. Clinical observations and results of gross necropsy are not specified.
Warheit. D.B. et al (2003): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. Instillation volume is not specified. Data on caging, humidity, temperature, acclimation period, and test group randomization are missing. Clinical observations and results of gross necropsy are not specified.
Ishihara, Y. et al. (1999): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. Test material is insufficiently characterized. Animal body weights are not stated. Historical data are missing. Details on animal husbandry are largely missing. No statements on caging, temperature, humidity, water and food supply, acclimation period, and test group randomization. Details in method section are missing. No statements on clinical observation and gross necropsy.
Foster, G.V. (1967): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. Test material is insufficiently characterized. Details in method section are missing. Details on animal husbandry are largely missing. No statements on caging, temperature, humidity, water and food supply, acclimation period, and test group randomization. The age of the rats used is not specified.
Schlesinger, S.J. (1969): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. Test material is insufficiently characterized. Details in method section are missing. Details on animal husbandry are largely missing. No statements on caging, temperature, humidity, water and food supply, and test group randomization. The age of the rats used is not specified.
Bergmann, J.D. et al. (2000): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. Test material is insufficiently characterized. Test animals are 14 weeks old at study initiation; however, the OECD recommends a maximum age of 12 weeks. Body weights at study initiation are not stated. Data on number of animals per cage is not stated. Room temperature for animal husbandry was 18.3°C, however the OECD recommends a temperature of 22 ± 3°C.
Wiecek, E. et al. (1978): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. Only abstract available. No conclusion can be drawn based on the restricted availability of information.
Yokohira, M. et al. (2009): The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. Test material characterisation is insufficient. The rats used were too young at study initiation (6 weeks); however the OECD recommends use of rats at a minimum age of 8 weeks. Concentration of the instillation stock solution is not specified. Pre-treatment with the carcinogen DHPN is inadequate and does not allow drawing any conclusion based on the generated results.
Harfoush, S.A. et al. (2020): The investigated mechanistic parameters (i.e. bronchoalveolar lavage (BAL) fluid analyses after intranasal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. The non-physiological route of administration via intranasal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Only one dose group was included, which precludes evaluation of dose-response relationships. The results observed in the asthmatic mice are not considered to be relevant due to the fact this type of test system is unsuitable. The test material preparation is insufficiently described. The test material was suspended in double distilled water. The test material TiO2 P25, however, is known for its acidic surface properties and could have potentially confounded the results obtained.
Halappanavar, S. et al. (2015):
The investigated mechanistic parameters (e. g. toxicogenomics, pathway studies) after intratracheal instillation of the test substance have no direct value for fulfilling data requirements under the REACH regulation. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Furthermore, some of the test items were not sufficiently characterised (paint dust, undefined mixture with unknown TiO2 content).
Yoshiura, Y. et al. (2015): The investigated mechanistic parameters (e. g. BALF analysis after intratracheal instillation of the test substance) have no direct value for fulfilling data requirements under the REACH regulation. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Moreover, an unknown number of animals were used and limited number of parameters were investigated.
Bonner, J. C. et al.(2013): The investigated mechanistic parameters (e. g. BALF analysis after intratracheal instillation / oropharyngeal aspiration of the test substance) have no direct value for fulfilling data requirements under the REACH regulation. The non-physiological route of administration via intratracheal instillation or oropharyngeal aspiration is not guideline conform and not suitable to assess acute inhalation toxicity. Furthermore, the most test items were not sufficiently characterised and limited number of parameters were investigated.
Höhr, D. et al. (2002): The investigated mechanistic parameters (e. g. BALF analysis after intratracheal instillation of the test substance) have no direct value for fulfilling data requirements under the REACH regulation. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Furthermore, the test substance is not sufficiently characterised and limited number of parameters were investigated.
Koizumi, A. et al. (1993):
The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Furthermore, the test substance is not sufficiently characterised. The study design (single administration and sacrifice 105 weeks post-exposure does not allow a conclusive statement neither for acute effects nor for chronic effects assessment.
Saber, A.T. et al.(2018):
The investigated mechanistic parameters (i. e. bronchoalveolar lavage (BAL) fluid analyses after intratracheal instillation of the test material) have no direct value for fulfilling data requirements under the REACH regulation, the methodical setup is not adequately designed for risk assessment purposes of the test substance. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Data is not shown on the publication. Body weights were not specified. Use of a cell line as positive control is not suitable to demonstrate accuracy of the test system. Cytotoxicity was not measured. Number of scored cells is not specified. These deficiencies in study design render the study of little relevance for risk assessment purposes.
Murugadoss, S. et al. (2020):
The investigated mechanistic parameters (e.g. BAL analysis after oropharyngeal aspiration of the test substance) have no direct value for fulfilling data requirements under the REACH regulation. The non-physiological route of administration via oropharyngeal aspiration is not guideline conform and not suitable to assess acute inhalation toxicity. The test items were not sufficiently characterised, especially information on the purity and coatings are missing. The administered concentrations are unclear because the concentrations were only given in the graphs and the shown unit of the values is incomplete. The information on test animals are largely missing, since details on the weights before and during and after the treatment, group assignment, group sizes in cages, feed and water availability, and acclimation period are not provided. The number of animals per group (n=4 or 5) is too low. Furthermore, the limited number of parameters were investigated.
Husain, M. et al. (2013):
The investigated mechanistic parameters (e. g. toxicogenomics, pathway studies) after intratracheal instillation of the test substance have no direct value for fulfilling data requirements under the REACH regulation. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity.
Choi, G.S. et al. (2014):
The investigated mechanistic parameters (e.g., BALF analysis after intratracheal instillation of the test substance) have, except for lung histopathology, no direct value for fulfilling data requirements under the REACH regulation. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Moreover, the animal number used (n = 3) is too low for robust statistics. The lungs that were lavaged in the first place were also subjected subsequently to histopathological examinations. No control-only animals were included, since the right lungs were always dosed with TiO2 P25, while the left side of the same lungs were treated with normal saline.
Hadrup, N. et al. (2017):
The investigated mechanistic parameter, i.e. BALF neutrophil count, after intratracheal instillation of the test substance have no direct value for fulfilling data requirements under the REACH regulation. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Only one dose level was tested precluding dose response relationship evaluation. Only females were used. The positive findings, observed 24 hours after the intratracheal instillations, are most likely attributable to bolus effects. The BALF neutrophil number was only specified as absolute count, whereas information with regard to neutrophil proportion among total cell number are missing.
Oyabu, T. et al. (2013):
The investigated mechanistic parameters (e.g. BALF neutrophil counts and cytokine levels) after intratracheal instillation of the test substance have no direct value for fulfilling data requirements under the REACH regulation. The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. Only males were used. The description of the test material preparation lacks details. The BALF neutrophil number was only specified as absolute count, whereas information with regard to neutrophil proportion among total cell number are missing. Prolonged neutrophilia was observed only at excessive TiO2 NP doses leading to lung overload conditions as indicated by the delayed clearance rates.
Han, B. et al. (2020):
The non-physiological route of administration via intratracheal instillation is not guideline conform and not suitable to assess acute inhalation toxicity. The test material was insufficiently characterised. Moreover, details on the test material preparation, including the vehicle used, are not provided. Only two dose group were included and only males were tested. The incidences and severity of the histopathological findings were not reported. Information on gross necropsy and clinical signs is missing.
Nishida, C. et al. (2020):
The study presented herein is a mechanistic study investigating on the correlation between chemokine expression and cellular influx in the alveolar space in order to find predictive biomarkers for pulmonary toxicity. Only two dose levels were tested. The histopathological examination is restricted to lung tissue in order to analyse cellular influx in the alveolar space. The test material was administered via intratracheal instillation, which is considered to be a non-physiological exposure route.
Summary entries - injection (subcutaneous, intravenous, intraperitoneal)
Several mechanistic studies investigated the toxic potential of ultrafine titanium dioxide following administration via subcutaneous, intravenous or intraperitoneal injection. All references do not fulfil the criteria for quality, reliability and adequacy of experimental data under REACH and for hazard assessment purposes. The following references are therefore reported as disregarded study records in summary entries, presenting some essential details for information purposes only:
Maltoni, C. et al. (1982) injected 30 mg suspended in 1 mL saline via single subcutaneous injection in 20 male and female Sprague-Dawley rats. Body weights, macroscopic lesions, histopathology of brain, thymus, mediastinal nodes, uterus, lung, liver, spleen, pancreas, kidneys, adrenals, stomach, subcutaneous and mesenteric nodes was conducted. The study shows significant methodological deficiencies in the experimental setup and documentation (only one dose administered, housing conditions not specified and the non-physiological route of administration via subcutaneous injection is not guideline conform and not suitable to assess acute toxicity). Furthermore, the test substance is not characterised.
Sha, B. et al. (2013) administered titanium dioxide via single intraperitoneal injection at doses of 0.5, 5 and 50 mg/kg BW to Sprague-Dawley rats. The study investigated mechanistic parameters (e. g. cytotoxicity in BRL-3A cells, effects following administration of alloxan in combination with TiO2 nanoparticles) have no direct value for fulfilling data requirements under the REACH regulation, since the methodical setup is not adequately designed for risk assessment purposes of the test substance. The non-physiological route of administration via intraperitoneal injection is not guideline conform and not suitable to assess acute toxicity, important details of the study design (e.g. number of animals, test item characterisation) were not specified.
Volkovova, K. et al. (2015) administered TiO2 P25 (Evonik Degussa, 15-16 nm) intravenously to female Wistar rats at doses of 35, 44, 55, 70, 139, 158 or 228 mg/kg bw. Mortality was recorded and histopathological examination of the liver of each animal and quantitative histological measurements were conducted. Fractional areas of the proportions of hepatocytes area and sinusoid space in the liver tissues were manually counted from a randomly selected area on a section from each animal.
The non-physiological route of administration via intravenous injection is not guideline conform and not suitable to assess acute toxicity. The publication shows significant methodological deficiencies in the experimental setup and documentation (unclear whether all administered doses were given, non GLP, only selected parameters investigated, insufficient information about test animals and environmental conditions) and the investigated endpoints are not required for building an expert judgment and further assessment of the test substance under REACH (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annex VII-X).
Justification for classification or non-classification
Acute oral toxicity
In each of the seven acute toxicity studies summarised above an LD50 > 2,000 mg/kg bw was derived for pigment grade and ultrafine titanium dioxide. The classification criteria acc. to regulation (EC) 1272/2008 as acutely toxic are not met since the ATE is above 2000mg/kg body-weight, hence no classification required.
Specific target organ toxicant (STOT) – single exposure: oral
The classification criteria acc. to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification of 300 mg/kg bw and at the guidance value, oral for a Category 2 classification of 2000 mg/kg bw. No classification required.
Acute inhalation toxicity
In the acute inhalation toxicity studies with titanium dioxide dust (pigment grade and ultrafine), rats were head and nose only exposed for 4 hours with up to 6.82 mg/L air. During the conduct of the studies no mortalities occurred. Therefore, the LC50 inhalation, rat was derived to be > 6.82 mg/L air.
The classification criteria according to regulation (EC) 1272/2008 as acutely toxic are not met since the ATE for dusts and mists is above 5.0 mg/L, hence no classification required.
Specific target organ toxicant (STOT) – single exposure: inhalation
The classification criteria acc. to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, inhalation dust/mist/fume are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, inhalation dust/mist/fume for a Category 1 classification of 1.0 mg/L/4h and at the guidance value, inhalation dust/mist/fume for a Category 2 classification of 5.0 mg/L/4h. Therefore, no classification is required.
Detailed epidemiological investigations have shown no causative link between titanium dioxide exposure and the risk of non-malignant respiratory disease or narcotic effects in humans. Animal data show evidence of transient respiratory irritant effects after acute inhalation exposure. However, category 3 is primarily to be based on human data. Animal data may be included in the weight of evidence evaluation.
Thus, no classification for STOT SE category 3 is justified according to the criteria of the CLP regulation.
Acute dermal toxicity
An acute dermal toxicity study with ultrafine titanium dioxide (purity 96.5%) coated with alumina/silica exists, providing a LD 50 > 2000 mg/kg bw.
Furthermore, dermal absorption through porcine or human skin in vitro and in vivo was negligible and titanium dioxide is of low systemic toxicity after single oral exposure (LD50 > 5,000 mg/kg bw in mice and rats). Therefore, the toxicological profile of this material does not give rise to concern in human use, since the substance is not absorbed through the skin and thus cannot lead to systemic effects after dermal exposure.
No classification for acute dermal toxicity is required as the ATE can safely be expected to be > 2000 mg/kg bw.
Specific target organ toxicant (STOT) – single exposure: dermal
There is no human data available, providing evidence that titanium dioxide elicits a specific target organ toxicity after single dermal exposure.
The Scientific Committee on Cosmetic Products and Non-food products intended for Consumers (SCCNFP, 2000) assessed the safety of titanium dioxide in cosmetic products, coming to the conclusion that the toxicological profile of this material does not give rise to concern in human use, since the substance is not absorbed through the skin. In view, also, of the lack of percutaneous absorption, a calculation of the margin of safety has not been carried out. This opinion concerns crystalline (anatase and/or rutile) titanium dioxide, whether or not subjected to various treatments (coating, doping, etc.), irrespective of particle size (covering pigment grade and ultrafine grades), provided only that such treatments do not compromise the safety of the product.
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.
![ECHA](/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/echa_logo.png)