NITE - Chemical Management Field

Latest GHS Classification Results by the Japanese Government (edited by NITE)

GENERAL INFORMATION

Item	Information
CAS RN	13463-67-7
Chemical Name	Titanium dioxide (nanoparticle)
Substance ID	m-nite-13463-67-7a_v1
Download of Excel format	Excel file

REFERENCE INFORMATION

Item	Information
Guidance used for the classification (External link)	To Guidance List
UN GHS document (External link)	To UN GHS document
FAQ（GHS classification results by the Japanese Government）	To FAQ
List of Information Sources (Excel file)	List of Information Sources
List of Definitions/Abbreviations	Definitions/Abbreviations
Sample Label by MHLW (External link)	MHLW Website (in Japanese Only)
Sample SDS by MHLW (External link)	MHLW Website (in Japanese Only)
OECD/eChemPortal (External link)	To OECD/eChemPortal (External link)

PHYSICAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
1	Explosives	Not classified (Not applicable)	- -	-	-	There are no chemical groups associated with explosive properties present in the molecule.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
6	Flammable liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
7	Flammable solids	Not classified	- -	-	-	It is not combustible (HSDB (Acess on May 2016)).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
8	Self-reactive substances and mixtures	Not classified (Not applicable)	- -	-	-	There are no chemical groups present in the molecule associated with explosive or self-reactive properties.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
10	Pyrophoric solids	Not classified	- -	-	-	It is not combustible (HSDB (Acess on May 2016)).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
11	Self-heating substances and mixtures	Not classified	- -	-	-	It is not combustible (HSDB (Acess on May 2016)).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
12	Substances and mixtures which, in contact with water, emit flammable gases	Not classified	- -	-	-	It is estimated that it does not react vigorously with water due to the observation result of being insoluble in water (ICSC (2002)).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
14	Oxidizing solids	Classification not possible	- -	-	-	It is an inorganic compound containing oxygen, but the classification is not possible due to no data.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	It is an inorganic compound.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
16	Corrosive to metals	Classification not possible	- -	-	-	Test methods applicable to solid substances are not available.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
17	Desensitized explosives	-	- -	-	-	-	-	-

HEALTH HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
1	Acute toxicity (Oral)	Not classified	- -	-	-	This classification was conducted for titanium dioxide particles in the range of 1 to 100 nm. 　　Based on the LD50 value of > 5,000 mg/kg (SIDS (2015)) for rats, it was classified as "Not classified."	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Dermal)	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Inhalation: Gases)	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Inhalation: Vapours)	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Inhalation: Dusts and mists)	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
2	Skin corrosion/irritation	Not classified	- -	-	-	Based on a report that no clear skin irritation was observed in the volunteer tests using an emulsion containing titanium dioxide nanoparticles and on a description that no skin irritation was observed in animals (OEL Documentations (Japan Society For Occupational Health (JSOH), 2013)), it was classified as "Not classified."	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
3	Serious eye damage/eye irritation	Not classified	- -	-	-	Based on a description that no eye irritation was observed in animals (OEL Documentations (Japan Society For Occupational Health (JDOH), 2013)), it was classified as "Not classified."	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
4	Respiratory sensitization	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
4	Skin sensitization	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
5	Germ cell mutagenicity	Classification not possible	- -	-	-	As for in vivo, micronucleus tests in peripheral erythrocytes of mice using anatase (75%)/rutile (25%) was positive, DNA damage tests in peripheral erythrocytes and liver of mice using anatase (75%)/rutile (25%) were positive, a Comet assay using the lung of rats was negative (crystal type of used nanoparticles was unknown) (OEL Documentations (Japan Society For Occupational Health (JSOH), 2013)), Risk Assessment Documents (National Institute of Advanced Industrial Science and Technology, 2011), DFGOT (2014), Environmental Risk Assessment for Chemical Substances vol. 8 (Ministry of the Environment, 2010), IARC 93 (2010)). In addition, a gene mutation test (gpt/liver, Pig-a/red blood cell), a micronucleus test (reticulocyte) and the comet assay (liver) by intravenous administration to transgenic mice using anatase (75%)/rutile (25%) were reported recently, and all tests results were negative (Mutation Research (2016)). As for in vitro, it was reported that in tests using anatase (100%), anatase (80%)/rutile (20%), rutile (100%), and anatase (70-85%)/rutile (30-15%), bacterial reverse mutation tests were negative, gene mutation tests using cultured mammalian cells such as primary cultured embryonic fibroblasts derived from gpt delta transgenic mice, micronucleus test of mammalian cultured cells and chromosome aberration test were positive or negative (OEL Documentations (Japan Society For Occupational Health (JSOH), 2013)), Risk Assessment Documents (National Institute of Advanced Industrial Science and Technology, 2011), IARC 93 (2010), Environmental Risk Assessment for Chemical Substances vol. 8 (Ministry of the Environment, 2010), DFGOT (2014)). It is concluded in Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013) that it was considered to be genotoxic from positive results in multiple in vitro micronucleus tests, in vivo micronucleus tests, etc., however, in genotoxicity of poorly soluble particles such as this substance, indirect (secondary) genotoxicity caused by free radicals was involved rather than direct action on the nucleus. 　From the above, positive result in vivo could not be regarded as definite finding because there are contradictory findings to positive in vivo findings observed so far, and it is evaluated that indirect (secondary) genotoxicity caused by free radicals was involved rather than direct action by this substance. Therefore, it was classified as "Classification not possible."	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	In a study in which female rats were exposed by inhalation to titanium dioxide nanoparticles (P25 (80% anatase/20% rutile, average primary particle size: 25 nm) at an average weight concentration of 10 mg/m3 for 2 years (18 hours/day, 5 days/week), the number of animals which developed lung tumors increased as 19/100 in the exposed group versus 1/217 in the non-exposed group. The breakdown of lung tumors was 3/100 for squamous cell carcinomas, 4/100 for adenomas, and 17/100 for adenocarcinomas (OEL Documentations (Japan Society For Occupational Health (JSOH), 2013), IARC 93 (2010)). In a study in which male and female rats were exposed by inhalation to titanium dioxide (crystalline type unspecified), 99% of which had a primary particle size of 0.5 micrometer, at 15.95 mg/m3 for 12 weeks (6 hours/day, 5 days/week) and tumor incidences were checked after 140 weeks, mortality was high (male: 88%, female: 90%), but in surviving animals, adenoma and squamous cell papilloma of the respiratory tract were observed in each one male, and bronchiolar alveolar adenoma was observed in one female (OEL Documentations (Japan Society For Occupational Health (JSOH), 2013), IARC 93 (2010)). Moreover, in a test using rats given two types of titanium oxide fine particles of P25 or AL23 (anatase, average particle diameter: 200 nm or less) by intratracheal administration at three or six times, high incidence of lung tumors was observed (OEL Documentations (Japan Society For Occupational Health (JSOH), 2013)). 　As described above, there were the evidences that titanium oxide nanoparticles showed carcinogenicity in experimental animals, and part of them was the evidence data based on which IARC classified titanium oxide in Group 2B. Therefore, the substance was classified in Category 2 for this hazard class.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
7	Reproductive toxicity	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
8	Specific target organ toxicity - Single exposure	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
9	Specific target organ toxicity - Repeated exposure	Category 1 (respiratory organs)	Danger	H372	P260 P264 P270 P314 P501	There is no information on humans. 　As for experimental animals, in studies in which rats, mice and hamsters were exposed by inhalation to titanium dioxide nanoparticles (particle size 21 nm, anatase 80%/rutile 20%) for 13 weeks (6 hours/day, 5 days/week) and pulmonary responses were measured at 4, 13, 26 and 52 weeks (49 weeks for hamsters) after the end of exposure, significant increases in total number of cells in bronchoalveolar lavage fluid (BALF), neutrophil count, macrophage count, and lymphocyte count as the fraction of BALF, LDH, protein concentration was observed at 10 mg/m3 (0.007 mg/L), which is equivalent to Category 1, and in rats and mice, pulmonary clearance was delayed, indicating that overload of titanium dioxide occurred (OEL Documentations (Japan Society For Occupational Health (JSOH), 2013), Environmental Risk Assessment for Chemical Substances vol. 8 (Ministry of the Environment, 2010), Risk Assessment Documents (National Institute of Advanced Industrial Science and Technology, 2011)). In addition, it was reported that in a 12-week (6 hours/day, 5 days/week) toxicity study using rats exposed by inhalation to 23 mg/m3 of titanium dioxide fine particles (particle diameter 250 nm, anatase type) or titanium dioxide nanoparticles (particle diameter 21 nm, anatase type), pulmonary inflammatory response appeared more strongly in the nanoparticle group, but after 64 weeks, it became almost the same as in the control group and exhibited reversibility at 23 mg/m3 (converted guidance value: 0.015mg/L), which is equivalent to Category 1 (Environmental Risk Assessment for Chemical Substances vol. 8 (Ministry of the Environment, 2010), Ferin, J. et al, Am J Respir Cell MoI Biol., 6, 535-542, (1992)). 　Therefore, it was classified in Category 1 (respiratory organ).	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
10	Aspiration hazard	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))

ENVIRONMENTAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
11	Hazardous to the aquatic environment Short term (Acute)	Classification not possible	- -	-	-	Because evaluation of the reliability of an ecological toxicity test using nanoparticles is not possible, it was classified as "Classification not possible."	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
11	Hazardous to the aquatic environment Long term (Chronic)	Classification not possible	- -	-	-	Because evaluation of the reliability of an ecological toxicity test using nanoparticles is not possible, it was classified as "Classification not possible."	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	No data available.	FY2016	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))

NOTE:

GHS Classification Result by the Japanese Government is intended to provide a reference for preparing a GHS label or SDS for users. To include the same classification result in a label or SDS for Japan is NOT mandatory.
Users can cite or copy this classification result when preparing a GHS label or SDS. Please be aware, however, that the responsibility for a label or SDS prepared by citing or copying this classification result lies with users.
This GHS classification was conducted based on the information sources and the guidance for classification and judgement which are described in the GHS Classification Guidance for the Japanese Government etc. Using other literature, test results etc. as evidence and including different content from this classification result in a label or SDS are allowed.
Hazard statement and precautionary statement will show by hovering the mouse cursor over a code in the column of "Hazard statement" and "Precautionary statement," respectively. In the excel file, both the codes and statements are provided.
A blank or "-" in the column of "Classification" denotes that a classification for the hazard class was not conducted in the year.
An asterisk “*” in the column of “Classification” denotes that “Not classified (or No applicable)” and/or “Classification not possible” is applicable. Details are described in the column of “Rationale for the classification”. If no English translation is available for “Rationale for the classification,” please refer to the Japanese version of the results.

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