Assessment - Titanium containing Substances Group
Environment and Climate Change Canada
Health Canada
June 2026
Synopsis
Pursuant to section 68 of the Canadian Environmental Protection Act, 1999 (CEPA), the Minister of the Environment and the Minister of Health have conducted an assessment of 13 substances referred to collectively as the Titanium-containing Substances Group. The Chemical Abstracts Service Registry Numbers (CAS RNsFootnote 1 ), Domestic Substances List (DSL) names, and common names of these substances are listed in the table below.
| CAS RN | DSL name | Common name |
|---|---|---|
| 546-68-9 | 2-Propanol, titanium(4+) salt | Titanium tetraisopropanolate |
| 1070-10-6 | 1-Hexanol, 2-ethyl-, titanium(4+) salt | Titanium tetrakis(2-ethylhexanolate) |
| 1317-80-2 | Rutile (TiO2) | Rutile (TiO2) |
| 1344-54-3 | Titanium oxide (Ti2O3) | Dititanium trioxide |
| 13463-67-7 | Titanium oxide (TiO2) | Titanium dioxide |
| 5593-70-4 | 1-Butanol, titanium(4+) salt | Titanium tetrabutanolate |
| 7550-45-0 | Titanium tetrachloride | Titanium tetrachloride |
| 7705-07-9 | Titanium chloride (TiCl3) | Titanium trichloride |
| 12047-27-7 | Titanate (TiO32-), barium (1:1) | Barium titanate (IV) |
| 12060-59-2 | Titanate (TiO32-), strontium (1:1) | Strontium titanium oxide |
| 13825-74-6 | Titanium, oxo[sulfato(2-)-O,O']- | Titanium oxide sulphate |
| 16919-27-0 | Titanate(2-), hexafluoro-, dipotassium, (OC-6-11)- | Dipotassium hexafluorotitanate |
| 20338-08-3 | Titanium hydroxide (Ti(OH)4), (T-4)- | Tetrahydroxytitanium |
The potential for cumulative effects was considered in this assessment by examining cumulative exposures to the moiety of titanium. Titanium is a naturally occurring metal that is present in the environment predominantly as titanium oxides. According to information submitted in response to a CEPA section 71 survey, 10 of the 11 surveyed titanium-containing substances in this group were manufactured or imported above the reporting threshold of 100 kg. Activities and uses involving these substances reported in Canada include metal mining and refining, processing intermediates, laboratory substances, fabric and textiles, adhesives and sealants, paints and coatings, water repellants, apparel and footwear care, automotive care, cleaning and furnishing care, building materials, floor coverings, food packaging materials, and electronics. In addition, some of the substances in the Titanium-containing Substances Group are permitted food additives. They are present in a range of products available to consumers, including self-care products (that is, cosmetics, natural health products, and non-prescription drugs), pest control products, do-it-yourself (DIY) products (for example, lubricants and greases, home maintenance products), cleaning products, plastics and rubber products, paper products, inks and printing supplies, toys, and arts and crafts products.
The ecological risks of the 13 titanium-containing substances were characterized using the Ecological Risk Classification of Inorganic Substances (ERC-I). ERC-I is a risk-based approach that employs multiple metrics considering both hazard and exposure, with weighted consideration of multiple lines of evidence for determining risk classification. Hazard characterization in ERC-I included a survey of published predicted no-effect concentrations (PNECs) and water quality guidelines, or the derivation of new PNEC values where required. Exposure profiling considered two approaches: predictive modelling using a generic near-field exposure model for each substance, and analysis of measured concentrations collected by federal and provincial water quality monitoring programs, with these concentrations used as a conservative indicator of exposure for individual substances. Measured and modelled predicted environmental concentrations were compared with PNECs, and multiple statistical metrics were computed and compared against decision criteria to classify the potential to cause harm to the environment. Based on the outcome of the ERC-I analysis, the 13 titanium-containing substances are considered unlikely to be causing ecological harm.
Considering all available lines of evidence presented in this assessment, there is low risk of harm to the environment from the 13 substances in the Titanium-containing Substances Group. It is concluded that the 13 substances in the Titanium-containing Substances Group do not meet the criteria set out in paragraphs 64(a) or (b) of CEPA as they are not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends.
People living in Canada may be exposed to substances in the Titanium-containing Substances Group through air, drinking water, food, soil, and house dust, as well as through the use of products available to consumers. Food is a major contributing source of exposure to titanium for the general population. In the absence of substance-specific exposure data, measured and modelled concentrations of titanium were used as surrogate data. Children between ages 4 and 13 years old had the highest estimated exposure to titanium from environmental media, food, and drinking water. Systemic exposure of the general population in Canada to substances in the Titanium-containing Substances Group was characterized using nationally representative titanium whole blood biomonitoring data from the Canadian Health Measures Survey (CHMS) Cycle 2 (2009 to 2011). Total titanium concentrations in whole blood provide a biologically relevant, integrated measure of systemic exposure resulting from multiple routes (for example, oral ingestion, dermal contact, and inhalation) and multiple sources (for example, natural and anthropogenic, environmental media, food, and frequent- or daily-use products). In the whole blood samples obtained from CHMS Cycle 2 (2009–2011), titanium was not detected at or above the limit of detection of 10 micrograms per litre (µg/L) in 99.97% of the Canadian population aged 3 to 79 years.
A no-observed-adverse-effect level (NOAEL) of 623 milligrams of titanium per kilogram of body weight per day (mg Ti/kg bw/day) (1,000 mg TiO2/kg bw/day) was considered to be the critical point of departure for risk characterization of systemic exposure. The NOAEL is based on lack of effects in multiple endpoints, including reproductive and developmental effects, developmental neurotoxicity, and the formation of aberrant crypt foci in the colon in an extended one-generation reproductive toxicity (EOGRT) study in rats exposed to food-grade titanium dioxide via diet. A biomonitoring equivalent (BE) of 65 µg/L was derived for the NOAEL from the EOGRT study. Titanium blood concentrations from the CHMS, based on the limit of detection of 10 µg/L, were below the BE of 65 µg/L and are considered to be low enough to account for uncertainties in the health effects and exposure data used to characterize risk. Therefore, at current levels of systemic exposure, the substances in the Titanium-containing Substances Group are considered to be of low concern to the health of the general population in Canada
With respect to inhalation exposure, non-cancer portal-of-entry effects in the respiratory system (that is, tracheitis, rhinitis with squamous metaplasia of the anterior nasal cavity, alveolar cell hyperplasia, and broncho/bronchiolar pneumonia) associated with titanium dioxide exposure in rats were identified as the critical health effect for chronic inhalation exposure. These portal-of-entry effects likely resulted from direct interaction of the substance with the lungs following chronic inhalation exposure. Lung tumours were noted in 2-year inhalation bioassays conducted in experimental animals. These lung tumours were not considered to be relevant to the general population, as tumours only occurred at doses that caused lung overload in experimental animals. Inhalation exposures from ambient air and the use of products available to consumers were quantified. The resulting margins of exposure estimated for inhalation exposure were considered adequate to address uncertainties in the health effects and exposure data used to characterize risk.
The human health assessment took into consideration those groups of individuals within the Canadian population who, due to greater susceptibility or greater exposure, may be more vulnerable to experiencing adverse health effects from exposure to substances. The health effects assessment took into consideration the potential for differences in kinetic behaviour or increased susceptibility to titanium-induced health effects associated with life stage (for example, the developing fetus), age, and sex. Exposure of infants and children, certain Indigenous populations, pregnant people, and people living in the vicinity of industrial point sources were considered in the human health assessment. Children were found to have higher exposure to titanium than adults from environmental media, food, and drinking water. Indigenous peoples, including pregnant people, from Northern Saskatchewan were found to have a lower dietary intake of titanium compared to the general population.
Considering all of the information presented in this assessment, it is concluded that the 13 substances in the Titanium-containing Substances Group do not meet the criterion set out in paragraph 64(c) of CEPA as they are not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.
It is therefore concluded that the 13 substances in the Titanium-containing Substances Group do not meet any of the criteria set out in section 64 of CEPA.
1. Introduction
Pursuant to section 68 of the Canadian Environmental Protection Act, 1999 (CEPA) (Canada 1999), the Minister of the Environment and the Minister of Health have conducted an assessment of 13 substances referred to collectively as the Titanium-containing Substances Group to determine whether these substances present or may present a risk to the environment or to human health. The substances in this group were identified as priorities for assessment because they met categorization criteria as described in Environment and Climate Change Canada (ECCC), Health Canada (HC) (modified 2017).
This group does not include all of the titanium-containing substances on the Domestic Substances List (DSL). This assessment only considers effects associated with titanium substances and does not address other elements or moieties that may be present in the substances of the Group (such as barium, fluoride, strontium, and organic-metal salts). Some of these other elements or moieties have been addressed through previous assessments via other initiatives of the Chemicals Management Plan (CMP). NanomaterialsFootnote 2 containing titanium (particles 1 nm to 100 nm) that may be present in environmental media, food or products are not explicitly considered in the exposure scenarios of this assessment, but measured concentrations of titanium in the environment or human biomonitoring data could include nanoscale titanium from these sources. Similarly, this assessment does not explicitly consider ecological or health effects associated with nanomaterials containing titanium. Nanomaterials can have different physicochemical and toxicological properties, as well as use patterns, compared with larger materials having the same chemical composition (also known as bulk materials). The Government of Canada has committed to addressing nanoscale forms of substances on the DSL, including nanoscale titanium dioxide, which will be considered in a future assessment (Health Canada [modified 2022a]; ECCC, HC 2022).
The ecological risks posed by the 13 substances in the Titanium-containing Substances Group were characterized using the Ecological Risk Classification of Inorganic Substances (ERC-I) (ECCC 2020). ERC-I is a risk-based approach that employs multiple metrics considering both hazard and exposure, with weighted consideration of multiple lines of evidence for determining risk classification. Hazard characterization in ERC-I included a survey of published predicted no-effect concentrations (PNECs) and water quality guidelines, or the derivation of a new PNEC value where required. Exposure profiling considered two approaches: predictive modelling using a generic near-field exposure model for each substance and analysis of measured concentrations collected by federal and provincial water quality monitoring programs, with metal concentrations used as a conservative indicator of exposure for individual substances. Measured and modelled predicted environmental concentrations (PECs) were compared with PNECs, and multiple statistical metrics were computed and compared against decision criteria to classify the potential to cause harm to the environment.
The human health risks of systemic exposure to substances in the Titanium-containing Substances Group were characterized using the Biomonitoring-based Approach 2 (Health Canada 2016a), which compares human biomonitoring data (exposure) against biomonitoring guidance values (health effects), such as biomonitoring equivalents (BEs), to assess whether substances are of low concern for human health. A route-specific approach was used to characterize portal-of-entry effects from the inhalation route of exposure for substances in the Titanium-containing Substances Group.
This assessment considers information on chemical hazards, uses, and exposures, including additional information submitted by stakeholders. Relevant data were identified up to June 2022. Empirical data from critical studies and results from models were used to reach conclusions. Where available and relevant, the information presented in assessments from other jurisdictions was considered.
This assessment was prepared by staff in the CEPA Risk Assessment Program at Health Canada and Environment and Climate Change Canada and incorporates input from other programs within these departments. The human health portion of this assessment has undergone external review and consultation. Comments on the technical portions relevant to human health were received from T. Lopez, J. Flippin, and J. Garey from Tetra Tech. The ecological portion of this assessment is based on the ERC-I Science Approach Document (published May 12, 2018), which was externally peer-reviewed and subject to a 60-day public comment period. The human health portion of this assessment is based in part on the Biomonitoring-based Approach 2 Science Approach Document (published December 9, 2016), which was subject to a 60-day public comment period. While external comments were taken into consideration, the final content and outcome of this assessment remain the responsibility of Health Canada and Environment and Climate Change Canada.
Assessments focus on information critical to determining whether substances meet the criteria as set out in section 64 of CEPA by considering scientific information, including information, if available, on subpopulations who may have greater susceptibility or greater exposure, vulnerable environments, and cumulative effectsFootnote 3 , and by incorporating a weight-of-evidence approach and precautionFootnote 4 . This assessment presents the critical information and considerations on which the conclusion is based.
2. Identity of substances
The Chemical Abstracts Service Registry Numbers (CAS RNs), DSL names, and common names for the 13 substances in the Titanium-containing Substances Group are presented in Table 2-1.
| CAS RN | DSL name | Common name |
|---|---|---|
| 546-68-9 | 2-Propanol, titanium(4+) salt | Titanium tetraisopropanolate |
| 1070-10-6 | 1-Hexanol, 2-ethyl-, titanium(4+) salt | Titanium tetrakis(2-ethylhexanolate) |
| 1317-80-2 | Rutile (TiO2) | Rutile (TiO2) |
| 1344-54-3 | Titanium oxide (Ti2O3) | Dititanium trioxide |
| 13463-67-7 | Titanium oxide (TiO2) | Titanium dioxide |
| 5593-70-4 | 1-Butanol, titanium(4+) salt | Titanium tetrabutanolate |
| 7550-45-0 | Titanium tetrachloride | Titanium tetrachloride |
| 7705-07-9 | Titanium chloride (TiCl3) | Titanium trichloride |
| 12047-27-7 | Titanate (TiO32-), barium (1:1) | Barium titanate (IV) |
| 12060-59-2 | Titanate (TiO32-), strontium (1:1) | Strontium titanium oxide |
| 13825-74-6 | Titanium, oxo[sulfato(2-)-O,O']- | Titanium oxide sulphate |
| 16919-27-0 | Titanate(2-), hexafluoro-, dipotassium, (OC-6-11)- | Dipotassium hexafluorotitanate |
| 20338-08-3 | Titanium hydroxide (Ti(OH)4), (T-4)- | Tetrahydroxytitanium |
3. Sources and uses
3.1 Natural sources
Titanium is a naturally occurring element. It is the ninth most abundant element in the earth’s crust and is found in many rocks and sediments worldwide (Woodruff et al. 2017). The mean concentration of titanium in soil is estimated at 0.33 weight percent globally (Woodruff et al. 2017). Titanium is not found naturally as a pure metal because it has a strong affinity for oxygen and typically forms oxide minerals (Woodruff et al. 2017; USGS 2018). Titanium minerals and materials of economic importance include ilmenite (FeTiO3) and the titanium dioxide polymorphs rutile, anatase, and brookite. Less common titanium minerals include pseudobrookite (Fe2TiO5), perovskite (CaTiO3), geikielite ((Mg,Fe)TiO3), pyrophanite (MnTiO3), and titanite or sphene (CaTiSiO5). The titanium content in titanium minerals ranges from approximately 2% to 20% .
3.2 Anthropogenic sources
3.2.1 Titanium production
Titanium is sourced from mineral deposits, extracted from the earth by the metal mining industry and further processed and refined by the metal smelting and refining industry. In 2019, Canada was the third largest producer of ilmenite globally, producing 9.9% of total global ilmenite (USGS 2020). There is one open cast titanium mine in Canada, located near Havre-Saint-Pierre, Québec, which produced 2,100,000 tonnes of magmatic ilmenite in 2019 (Rio Tinto 2019a). The ilmenite ore is processed into titanium slag, which is used to produce titanium dioxide products, at a nearby associated metallurgical complex in Sorel-Tracy, Québec (Rio Tinto 2019b). This metallurgical complex in Sorel-Tracy, Québec, produced 800,000 tonnes of titanium slag in 2019. The titanium industry is currently limited to a few facilities in Canada but has the potential to expand owing to new technologies for extracting titanium from heavy mineral sands and non-conventional ore minerals, as well as potential increases in global demand for titanium metal and titanium dioxide (USGS 2013; Woodruff et al. 2017).
3.2.2 Manufacture and imports
Of the 13 substances in the Titanium-containing Substances Group, 11 have been included in surveys issued pursuant to a CEPA section 71 notice (Canada 2012). Table 3‑1 presents a summary of the information reported on the total manufacture and import quantities for these substances in Canada for the 2011 reporting year. Rutile titanium dioxide (CAS RN 1317-80-2) and titanium dioxide (CAS RN 13463-67-7) were not included in the survey because they were already known to be imported in high quantities in Canada. Data for relevant harmonized system (HS) codes indicate that approximately 10,000,000 kg to 100,000,000 kg were imported annually between 2010 and 2013 (CIMTWA [modified 2022b]).
| DSL name | CAS RN | Total manufacturea (kg) | Total importsa (kg) |
|---|---|---|---|
| 2-Propanol, titanium(4++) salt | 546-68-9 | NR | 1,000 to 10,000 |
| 1-Hexanol, 2-ethyl-, titanium(4+) salt | 1070-10-6 | 100 to 1,000 | 1,000 to 10,000 |
| Titanium oxide (Ti2O3) | 1344-54-3 | NR | 10,000 to 100,000 |
| 1-Butanol, titanium(4+) salt | 5593-70-4 | NR | 1,000 to 10,000 |
| Titanium tetrachloride | 7550-45-0 | Over 10,000,000 | 10,000 to 100,000 |
| Titanium chloride (TiCl3) | 7705-07-9 | 1,000 to 10,000 | 1,000 to 10,000 |
| Titanate (TiO32-) barium (1:1) | 12047-27-7 | NR | 1,000 to10,000 |
| Titanate (TiO32-), strontium (1:1) | 12060-59-2 | NR | NR |
| Titanium, oxo[sulfato(2-)-O,O']- | 13825-74-6 | 100,000 to 1,000,000 | NR |
| Titanate(2-), hexafluror-, dipotassium, (OC-6-11)- | 16919-27-0 | NR | 100 to 1,000 |
| Titanium hydroxide (Ti(OH)4), (T-4)- | 20338-08-3 | NR | 100 to 1,000 |
Abbreviations: NR, not reported above the reporting threshold of 100 kg
a Values reflect quantities reported in response to surveys issued pursuant to section 71 of CEPA (Environment Canada 2013). See surveys for specific inclusions and exclusions (Schedules 2 and 3).
Import and export quantities from the Canadian International Merchandise Trade Web Application (CIMTWA) were considered to identify quantities imported and exported in Canada in recent years. Import and export quantities from 2017 to 2021 for three titanium-containing HS 6 codes relevant to the 13 titanium-containing substances in this assessment (listed in Table 3-2) were considered (CIMTWA [modified 2022a]). The three relevant HS 6 codes include titanium oxides and titanium pigments, trade commodities that may be sources of the substances in the Titanium-containing Substances Group. From 2017 to 2021, Canada imported 6,961,041 kg to 82,402,444 kg of relevant titanium commodities per year and exported 6,842,492 kg to 110,676,653 kg of relevant titanium commodities per year (Table 3‑2) (CIMTWA [modified 2022a]).
| HS 6 code name | HS code | Average quantity imported per year (kg) | Average quantity exported per year (kg) |
|---|---|---|---|
| Titanium oxides | 2823.00 | 7,373,585 | 6,842,492 |
| Containing 80% or more by weight of titanium dioxide, calculated on the dry matter | 3206.11 | 82,402,444 | 110,676,653 |
| Pigments and preparations, based on titanium dioxide, nes | 3206.19 | 6,961,041 | 12,800,515 |
Abbreviations: HS 6, six-digit Harmonized System code; kg, kilograms; nes, not elsewhere specified
3.2.3 Uses
Titanium dioxide, titanium tetrachloride, and titanium trichloride are the most abundant titanium compounds in commerce, with titanium dioxide representing 95% of all titanium consumed (Jin and Berlin 2015; Ramoju et al. 2020). The principal use of titanium mineral is for the manufacture of titanium dioxide pigment, which accounts for more than 90% of world titanium mineral consumption (Murphy and Frick 2006 as cited in Woodruff et al. 2017). Titanium metal and alloys have a number of uses in transportation and the chemical industry, as well as in pulp and paper and medical applications owing to their properties, which include high tensile strength, light weight, chemical inertness, and high corrosion resistance (Jin and Berlin 2015).Titanium dioxide pigment is commonly used in paints and coatings, plastics, cosmetics, and drug products available to consumers due to its low price, high availability, brightness/whiteness, and high index of refraction (Jin and Berlin 2015).
According to information submitted in response to a CEPA section 71 survey, substances in the Titanium-containing Substances Group are used in various industrial, commercial, and consumer applications (Environment Canada 2013). Activities or uses reported in response to the survey for substances associated with quantities over 1,000 kg in the reporting year include processing intermediates, laboratory substances, fabric and textiles, adhesives and sealants, paints and coatings, and water repellants. Activities or uses reported in response to the survey for substances associated with lower quantities (less than 1,000 kg in the reporting year) include apparel and footwear care, automotive care, cleaning and furnishing products, building materials, floor coverings, food packaging materials, and electronics. Other uses reported in response to the CEPA section 71 survey beyond those identified here were notified as confidential business information.
Further literature searches indicate that substances in the Titanium-containing Substances Group may also be present in cleaning products, laundry products, dish care products, plastics and rubber products, paper products, catalysts, ceramics, printing ink, stationery products, aerospace applications, marine applications, medical applications, oil and gas products, and specialty chemicals (Woodruff et al. 2017; Health Canada 2019; USGS 2020; CPID [modified 2022]; CPISI [modified 2022]).
Substances in the Titanium-containing Substances Group are also found in arts and crafts materials and toys, such as paints, chalks, glue, clays, and crayons (Health Canada 2019; SCHEER 2023). In 2023, the European Commission evaluated the use of titanium dioxide in toys and toy materials (SCHEER 2023). The uses identified in the resulting scientific opinion are considered to be consistent with uses in arts and crafts materials and toys in Canada and are therefore considered in this assessment.
Substances in the Titanium-containing Substances Group are present in cosmetics based on notifications submitted under the Cosmetic Regulations (personal communication, emails from the Consumer and Hazardous Products Safety Directorate [CHPSD], Health Canada, to the Existing Substances Risk Assessment Bureau [ESRAB], Health Canada, dated between March 29, 2018, and December 8, 2020; unreferenced).The substances in this group are also present as medicinal or non-medicinal ingredients in disinfectants and human and veterinary drug products, as well as in natural health products (personal communication, emails from the Pharmaceutical Drugs Directorate [PDD], Health Canada, to the ESRAB, Health Canada, dated February 16, 2018, and February 26, 2018; unreferenced; personal communication, email from the Natural and Non-prescription Health Products Directorate [NNHPD], Health Canada, to the ESRAB, Health Canada, dated March 9, 2018; unreferenced; DPD [modified 2022]; LNHPD [modified 2024]; NHPID [modified 2024]).
Titanium and its alloys are used in medical procedures, such as dental implants and hip replacements. Health effects related to these uses were not considered in this assessment.
In Canada, substances in the Titanium-containing Substances Group may be used as components in the manufacture of food packaging materials (personal communication, email from the Food and Nutrition Directorate [FND], Health Canada, to the ESRAB, Health Canada, dated March 13, 2018; unreferenced). Titanium-containing food additives (titanium dioxide, potassium aluminium silicate-based titanium dioxide, and potassium aluminum silicate-based titanium dioxide and iron oxide) are permitted for use as colouring agents in a variety of foods, as set out in the List of Permitted Food Colours, incorporated by reference under the Food and Drug Regulations (Health Canada [modified 2024]). Uses of food-grade titanium dioxide as food additives have been evaluated by Health Canada’s Food and Nutrition Directorate in the State of the Science of Titanium Dioxide (TiO2) as a Food Additive, which was published in June 2022 (Health Canada 2022b). In this report, Health Canada’s Food and Nutrition Directorate did not identify any conclusive scientific evidence that the food additive titanium dioxide is a concern for human health. Health Canada’s Food and Nutrition Directorate will continue to monitor emerging scientific evidence related to the safety of food uses of titanium dioxide.
Additionally, some substances in the Titanium-containing Substances Group are present in registered pest control products in Canada as formulants (personal communication, email from the Pest Management Regulatory Agency, Health Canada, to the ESRAB, Health Canada, dated January 31, 2018; unreferenced).
4. Potential to cause ecological harm
The potential for cumulative effects was considered in this assessment by examining cumulative exposures to the moiety of titanium. The ecological risks of the 13 substances in the Titanium-containing Substances Group were characterized using the ERC-I (ECCC 2020). ERC-I is a risk-based approach that employs multiple metrics considering both hazard and exposure, with weighted consideration of multiple lines of evidence for determining risk classification. A summary of the approach is outlined below; the approach is described in detail in the ERC-I Science Approach Document (ECCC 2020). Engineered nanomaterial forms of these substances were not explicitly considered in the exposure scenarios of the ERC-I approach. While measured concentrations in the environment could include engineered nanomaterial forms of these substances, engineered nanomaterial forms may be subject to separate assessment, considering their unique properties. Therefore, this ecological assessment does not explicitly consider the ecological harm associated with nanomaterials containing titanium.
Characterization of ecological risk
Hazard characterization in ERC-I included a survey of published PNECs and water quality guidelines from domestic and international assessments. Where no suitable existing PNEC or water quality guideline was found, hazard endpoint data were collected and, depending on data availability, a species sensitivity distribution or an assessment factor (AF) approach was taken to derive a new PNEC value. In the case of the 13 titanium-containing substances, hazard endpoint data were available from multiple sources, including comprehensive literature searches for specific groups, targeted searches of the ECOTOX database, and European Chemicals Agency (ECHA) registration dossiers (as described in ECCC [2020]). In the absence of more recent information, the assumptions used in the 2006 categorization of the DSL were also considered (ECCC, HC [modified 2017]). An AF approach was used to derive a PNEC value of 850 µg/L for titanium and a PNEC value of 2,760 µg/L for titanium dioxide (ECCC 2020).
Background concentrations were not used in PEC modelling for ERC-I (Kilgour & Associates Ltd. 2016; Appendix B of the ERC-I document (ECCC 2020). However, the titanium PNEC derived for ERC-I was well above background concentrations. As such, risk quotients would have been minimally sensitive to the absence of background concentrations in PEC modelling.
Exposure profiling in ERC-I considered two approaches: predictive modelling using a generic near-field exposure model, and an analysis of measured concentrations collected by federal and provincial water quality monitoring programs. The generic near-field exposure model used input data, where available, from the National Pollutant Release Inventory (NPRI), information submitted in response to CEPA section 71 surveys, international trade data from the Canada Border Services Agency (CBSA), and third-party market research reports to generate PECs. In the case of the 13 titanium-containing substances, information submitted in response to a CEPA section 71 survey and international trade data from the CBSA were available. Data were available from the NPRI for titanium tetrachloride (as described in ECCC [2020]).
Measured titanium concentrations for total and dissolved titanium were available from the National Long-term Water Quality Monitoring (NLTWQM) network, the Environmental Monitoring System of the British Columbia Ministry of the Environment and Climate Change Strategy, the Surface Water Quality Program of Alberta Environment and Parks, the Regional Aquatics Monitoring Program, the Canada–Alberta Joint Oil Sands Environmental Monitoring Program, the Long Term Water Quality Monitoring Network of the Government of Manitoba, the Provincial Water Quality Monitoring Network of the Ontario Ministry of the Environment and Climate Change, and the Baseline Monitoring of Lower Order Streams in Saskatchewan. Extractable titanium concentrations were available and compiled from the NLTWQM network for the Atlantic, Pacific, and Northwest Territories regions between 2005 and 2015. Exposure profiling using modelled and measured data for the 13 titanium-containing substances resulted in a low exposure classification for each substance.
Measured values and modelled PECs were compared with the PNECs, and statistical metrics that consider both the frequency and magnitude of exceedances were computed and compared against decision criteria to classify the potential for ecological risk. Critical data and the considerations used to create substance-specific ecological profiles and classifications associated with ecological risk, as well as the identification of the potential need to track future use patterns, are presented in ECCC (2020). According to information considered in ERC-I, the overall risk classification for each of the 13 substances in the Titanium-containing Substances Group is low. Based on the outcome of the ERC-I analysis, the 13 titanium-containing substances are considered unlikely to be causing ecological harm.
5. Potential to cause harm to human health
This human health assessment includes characterization of hazard and exposure to microscale (≥0.1 µm) forms of substances in the Titanium-containing Substances Group. This human health assessment does not explicitly consider the health effects associated with nanomaterials containing titanium. However, health effects from exposure to titanium-containing substances that include both microscale and nanoscale particles (for example, food-grade titanium dioxide) were considered in this human health assessment. The approach used to assess the toxicokinetic and systemic effects of oral exposure to microscale titanium dioxide was primarily based on the State of the Science published by Health Canada’s Food and Nutrition Directorate (Health Canada 2022b).
It should be noted that analytical methodologies used to determine particle sizes of titanium-containing substances across different studies have changed over time.
5.1 Health effects assessment
According to a literature search of the 13 titanium-containing substances in this assessment, toxicokinetic and toxicity data for oral, dermal, and inhalation routes were predominantly available for titanium dioxide, including the rutile and anatase forms. Thus, toxicokinetic and toxicity data for titanium dioxide were used as surrogate data for all substances in the Titanium-containing Substances Group.
Several national and international organizations have reviewed the health effects of exposure to titanium-containing substances (that is, titanium dioxide) in the general population (IPCS 1982; NSF 2005; ECETOC 2013; OECD 2013; Ontario 2014; CLH 2016; EFSA 2016, 2021; NICNAS 2016; ECHA 2017; SCCS 2020; FSANZ 2022; Health Canada 2022b; JECFA 2024). The health effects of workers exposed to titanium dioxide in occupational settings were also assessed by several international organizations, including the American Conference of Governmental Industrial Hygienists (ACGIH 2009), the International Agency for Research on Cancer (IARC 2010), and the National Institute for Occupational Safety and Health (NIOSH 2011).
The key hazard assessments on titanium dioxide for the general population are summarized below.
In 2005, the National Sanitation Foundation (NSF) International (NSF 2005) derived a reference dose (RfD) for titanium based on a 1979 study by the National Cancer Institute (NCI). The NSF (2005) identified the highest dietary titanium dioxide concentration administered (that is, 50,000 parts per million (ppm), 5% weight by weight (w/w) TiO2) as a no-observed-adverse-effect level (NOAEL). This NOAEL was equivalent to 2,680 mg Ti/kg bw/day, which was estimated based on the average food intake and body weights of female F344 rats. The NSF (2005) calculated a RfD of 2.7 mg Ti/kg bw/day using the above NOAEL and an uncertainty factor (UF) of 1,000, which included UFs for interspecies extrapolation (10) and intraspecies variation (10), as well as an additional uncertainty factor (UF) of 10 to account for database deficiencies, including a lack of developmental and reproductive toxicity studies.
In March 2020, the European Commission requested that the European Food Safety Authority (EFSA) conduct a new risk assessment for E171Footnote 6 to address any potential uncertainties, including in vivo genotoxicity (EFSA 2019a, 2019b). As a result, EFSA initiated a reassessment of food-grade titanium dioxide, E171. E171 has been shown to have a high prevalence of nanoscale particles, which may lead to adverse health effects (Bischoff et al. 2021). The final EFSA assessment was published in May 2021. Based on the uncertainties in the available information on the particle distribution and health effects analysis, the EFSA Panel on Food Additive and Nutrient Sources Added to Food concluded that “E171 can no longer be considered as safe when used as a food additive” (EFSA 2021). Due to the above-listed uncertainties in the health effects data set associated with titanium dioxide (E171) food additives, EFSA (2021) did not derive an exposure guidance value. The EFSA (2021) conclusion was predominantly based on evidence from studies conducted using nanoscale titanium dioxide or studies where E171 was present in simpler matrices that used sonication techniques for particle dispersion.Bevilacqua et al. (2024). The authors.
Scientific Committee on Consumer Safety (SCCS (2023) considered that the available data were insufficient to exclude the genotoxicity potential of titanium dioxide used in oral cosmetic products, and it recommended further studies.
In June 2022, Health Canada’s Food and Nutrition Directorate published a State of the Science concerning the safety of titanium dioxide as a food additive (Health Canada 2022b). The State of the Science presents the safety assessment of the use of titanium dioxide as a food additive based on an in-depth review of available toxicokinetic and hazard data for titanium dioxide, including several significant new pieces of information that were not available to the EFSA (2021) at the time of their assessment. The review focused on studies conducted with food-grade titanium dioxide (also referred to as E171, according to European labelling requirements for food additives), which is a mixture of nanoscale and microscale titanium dioxide particles (Health Canada 2022b). After reviewing the available data, the Health Canada Food and Nutrition Directorate’s State of the Science determined that “there is no conclusive scientific evidence that the food additive titanium dioxide is a concern for human health.” Food Standards Australia New Zealand (FSANZ 2022) and the United Kingdom (UK) Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT 2022) came to similar conclusions. The Joint Food and Agriculture Organization / World Health Organization Expert Committee on Food Additives (JECFA) also conducted an assessment of the health impacts of the food additive titanium dioxide in November 2023 and found no evidence of an identifiable hazard associated with its use as a food additive. The JECFA committee also determined that the available genotoxicity data did not provide convincing evidence of the genotoxicity of food-grade titanium dioxide. However, the committee acknowledged that there are limitations to the current testing methodologies for poorly soluble particulate materials (JECFA 2024).
Information for the health effects section of this assessment was predominantly obtained from existing assessments, and primary literature was reviewed where needed.
5.1.1 Toxicokinetic data and biomarker adequacy
The toxicokinetic data described in this section were primarily limited to those conducted on microscale (≥100 nm) titanium-containing substances. In general, titanium absorption from the gastrointestinal tract (GIT) is low in humans and experimental animals (Perry and Perry 1959; Schroeder et al. 1963; MacNicoll et al. 2015; Farrell and Magnuson 2017; Winkler et al. 2018; Health Canada 2022b). Jones et al. (2015) estimated less than 0.1% of maximum oral absorption when human volunteers were given a single dose of 5 mg TiO2/kg bw (< 5,000 nm) dispersed in water. Based on the data obtained from repeated oral administration of titanium dioxide (particle size of 500 nm) to rats for 10 days, Jani et al. (1994) proposed a blood uptake of 0.02%. The study also estimated an oral absorption of 6.5% after accounting for the total tissue distribution of titanium (Jani et al. 1994). Similarly, after repeated oral administration of different titanium dioxide nanomaterials , Geraets et al. (2014) estimated approximately 0.02% oral absorption in rats based on the total recovery of titanium in all tested organs (that is, liver, spleen, and mesenteric lymph nodes). The nominal particle size of the test materials in this study ranged from 7 nm to 220 nm, whereas the mean particle size ranged from 38 nm to 267 nm. This estimate by Geraets et al. (2014) is in line with the absorption fraction of micro titanium dioxide reported by Jani et al. (1994). Other authors indicated a lack of oral absorption based on insignificant translocation of titanium microparticles from the GIT to other tissues after a single administration of microscale titanium dioxide (particle sizes of 120 and 5,000 nm) to rats (MacNicoll et al. 2015) or repeated administration to rats or mice (particle sizes ranging up to 250 nm) (Farrell and Magnuson 2017; Yan et al. 2020). After evaluating the body of evidence available for titanium absorption, EFSA (2016) determined that the oral bioavailability of titanium (measured as titanium dioxide) ranges from 0.02% to 0.1%. Based on the assumptions that the majority of titanium in the body is present in the liver and spleen and that all titanium in the body is derived from dietary sources (that is, from the use of titanium dioxide as a food additive), EFSA (2021) estimated the oral systemic availability of titanium dioxide in humans to be less than 1%, at most. Of note, most of these toxicokinetic studies focused primarily on the kinetic properties of nanoscale titanium dioxide (for example, Geraets et al. 2014; Jones et al. 2015).
Titanium absorption from the GIT occurs as a bi-modal pattern in humans, with peaks reported at approximately 2 and 6 hours following intake of titanium dioxide (particle sizes ranged from 160 nm to 380 nm) (Böckmann et al. 2000; Pele et al. 2015). Early absorption is most likely from the proximal region of the small intestine (that is, duodenum and jejunum), while late absorption is expected from the distal region (Pele et al. 2015)., Using microscopic imaging, several authors reported that uptake of titanium from food-grade titanium dioxide (E171) through Peyer’s patches (gut-associated lymphoid tissue) in the distal region (ileum) of the small intestine (Shepherd et al 1987; Pele et al. 2015; Bettini et al. 2017; Coméra et al. 2020; Riedle et al. 2020). Bettini et al. (2017) suggested that titanium dioxide may also be absorbed from the colon in rats exposed to E171.
In experimental animals, the rate of oral absorption is likely determined by particle size. Smaller particle sizes were noted to have faster absorption rates than larger particles in experimental animal studies; however, the effect of particle size on absorption rate in humans has not been clearly demonstrated (DFG 2014; Jones et al. 2015). Available data suggest that physiological conditions (for example, stomach pH) do not affect the solubility of titanium (Winkler et al. 2018).
No dermal penetration by microscale titanium dioxide was detected in available in vivo (humans or experimental animals) or in vitro (human skin penetration tests) data (Pflücker et al. 2001; Mavon et al. 2007; Sadrieh et al. 2010).
There was no convincing evidence for systemic absorption of titanium particles via the respiratory tract (DFG 2014). However, prolonged retention of inhaled particles was observed in experimental animals (Bermudez et al. 2002). Retention time depends on the exposure concentration and the species tested (Bermudez et al. 2002).
Following ingestion of titanium dioxide (particle size of 155 nm), the highest concentrations were reported in the spleen, followed by the lungs and brain (Wang et al. 2007; EFSA 2016, 2021). After single or repeated intravenous (i.v.) injections of pigment-grade titanium dioxide (mean particle size of 267 nm), accumulation was highest in the liver, followed by the spleen, lungs, and kidneys (Geraets et al. 2014). Some human and animal studies conducted with microscale titanium administered via the oral route have reported relatively high titanium concentrations in the lungs, probably due to the retention of inhaled titanium from contaminated environmental dust (Schroeder et al. 1963; Wang et al. 2007). After analyzing human placentas (n=22) and meconium samples (n=18), Guillard et al. (2020) showed that a small concentration of ingested titanium may be systemically available to the developing fetus. However, this study did not control for titanium contamination from diapering products, and the titanium concentrations detected in the fetal exudates were within the range of those detected in the blanks. Using an ex vivo human placental perfusion model, the authors further demonstrated that a small amount of titanium dioxide (E171) (55% nanoscale particles, measured by scanning electron microscopy [SEM]) could cross placental membranes to the fetal side. Additional analysis revealed that 75% to 100% of particles transferred to the fetal side were in the nano-sized range.
Over 96% of orally administered titanium (predominantly as titanium dioxide) is unabsorbed and excreted in the feces (Schroeder et al. 1963; Jovanović 2014; Jin and Berlin 2015). Of the orally absorbed fraction of microscale titanium, less than 2% is excreted in the urine of experimental animals and less than 3% in the urine of humans, with the remainder eliminated in feces (Perry and Perry 1959; Schroeder et al. 1963; EFSA 2016, 2021; Farrell and Magnuson 2017). Clearance of titanium from the body is prolonged; the biological half-life for titanium was estimated to be, on average, 320 days or longer in humans, 640 days in mice, and 450 days in rats (IPCS 1982; Geraets et al. 2014; Jin and Berlin 2015). Some authors have indicated that titanium dioxide may interact with gut microbiota prior to elimination (Pinget et al. 2019; Talamini et al. 2019; Lamas et al. 2020). EFSA (2021) considered that current knowledge was insufficient to make any conclusions regarding the effects of E171 on gut microbiota and related health effects.
The retention half-life of inhaled titanium dioxide varies with particle size and concentration (Kawasaki 2017). In rats, the lung retention half-lives of microscale particles (rutile; the mass median aerodynamic diameter [MMAD] of particle size was 144 nm) were 100, 324, and 838 days for exposure concentrations of 10, 50, and 250 mg/m3, respectively (Bermudez et al. 2002). Warheit et al. (1997) reported somewhat shorter retention times than Bermudez et al. (2002). According to Warheit et al. (1997), titanium dioxide (four-week exposure, pigment-grade rutile type, primary particle size of 200 nm to 300 nm) deposited in rat lungs was cleared with elimination half-lives of 68, 110, and 330 days for the 5, 50, and 250 mg/m³ groups, respectively. EFSA (2016) further proposed that the slow elimination of titanium likely indicates a potential for slow but steady titanium accumulation in the body.
The concentration of titanium in blood represents the bioavailable fraction, which is the fraction systemically available at target sites. Continuous exposure is expected in the general population because the primary sources of titanium exposure are food and environmental media, and frequent dietary exposure to titanium is likely to result in steady-state titanium concentrations in blood. Dosing studies in humans and animals show measurable increases in blood titanium concentrations following oral ingestion of known quantities of food-grade titanium dioxide (primarily microscale particles) (Ramoju et al. 2020). Böckmann et al. (2000) reported peak blood concentrations of 43.2 (n=5) and 61.8 μg/L (n=2) after administering capsules containing 22.9 or 45.8 mg of microscale titanium dioxide, respectively. Using a comparable trial design involving human volunteers, Pele et al. (2015) reported a similar pattern of titanium absorption into the blood following oral administration. A small but dose-related increase in blood titanium concentration was also reported in some treated groups in an extended one-generation reproductive toxicity (EOGRT) study in rats (REACH [modified 2022]). Thus, for the purposes of this human health assessment, the titanium concentration in whole blood is considered a suitable biomarker to quantify systemic exposure from all routes and sources of titanium. Of note, the predominant route of systemic exposure to titanium-containing substances in the general population is likely the oral route from dietary sources.
5.1.4 Health effects of oral exposure to titanium
Titanium is not considered an essential element, and titanium consumption has no beneficial effects for humans (IPCS 1982). In this assessment, it is assumed that titanium is the toxicologically relevant moiety for the systemic health effects of titanium-containing substances. Where applicable, administered or systemically exposed doses from titanium-containing substances were converted to equivalent elemental titanium doses using molecular weight conversion.
Acute toxicity
Two studies, conducted according to the Organisation for Economic Co-operation and Development (OECD) test guidelines (TGs) 420 (in male and female mice) and 425 (in female rats), reported an acute oral median lethal dose (LD50) of greater than 5,000 mg TiO2/kg bw (3,114 mg Ti/kg bw) (OECD 2013). EFSA (2016) reported LD50 values for titanium dioxide in mice and rats of >10 g TiO2/kg bw and >25,000 mg TiO2/kg bw, respectively.
Wang et al. (2007) did not report significant changes in body weight or organ weights (that is, liver, spleen, and kidneys) or serum biochemical parameters in male and female Charles River (CD-I) mice at 2 weeks following exposure to a single oral gavage dose of microscale titanium dioxide (particle size of 155 nm) at 5,000 mg TiO2/kg bw (3,114 mg Ti/kg bw) compared to control animals. There were no adverse pathological changes in the heart, lung, testicles or ovaries, or the spleen tissue of treated male and female mice. However, histopathological evaluation of treated male and female animals indicated fatty degeneration induced in the hippocampus, swelling in the renal glomerulus, spotty necrosis of hepatocytes (female only), and hydropic degeneration around the central vein of the liver. While the authors reported that these effects were found for both nanoscale and microscale particles (80 and 155 nm, respectively), EFSA (2016) indicated that the above effects were only associated with nanoscale particles (80 nm).
Based on the available key reviews (OECD 2013; EFSA 2016, 2021), microscale titanium exhibits low acute toxicity via the oral route.
Short-term and sub-chronic toxicity
In a 28-day study (OECD TG 407), male Sprague-Dawley (SD) rats were administered one of two types of rutile pigment-grade titanium dioxide (median particle size [D50] of 173 nm) at a dose of 24,000 mg/kg bw/day (equivalent to 14,946 mg Ti/kg bw/day) via oral gavage. No significant changes in body and organ weights or gross pathology were observed, and the authors concluded that the dose tested was the NOAEL (OECD 2013; Warheit et al. 2015b).
The same authors conducted a 90-day toxicity study following OECD TG 408. Male and female SD rats were administered surface-coated pigment-grade titanium dioxide (D50 of 145 nm by number) at 0, 100, 300, or 1,000 mg/kg bw/day (0, 62, 187, or 623 mg Ti/kg bw/day, respectively) by oral gavage. Animals were evaluated for food consumption, body weight, neurobehavioural effects, clinical pathology, hematology, clinical serum chemistry, and urinalysis. None of the exposed animals showed any significant treatment-related effects; therefore, the authors determined that the NOAEL for 90-day exposure was 623 mg Ti/kg bw/day (Warheit et al. 2015b).
Another 90-day range-finding study for chronic carcinogenicity, conducted by the NCI (1979), analyzed the toxicity of anatase titanium dioxide in Fischer 344 rats. Rats (10/sex/dose) were administered titanium dioxide at doses of 6,250, 12,500, 25,000, 50,000, or 100,000 mg/kg in the diet (equivalent to 569, 1,138, 2,275, 4,550, or 9,100 mg TiO2/kg bw/day for female rats and 506, 1,013, 2,025, 4,050, or 8,100 mg TiO2/kg bw/day for male rats, respectively; dose conversion as per EFSA [2016]). The original study did not report particle sizes; however, the Health Canada Food and Nutrition Directorate’s State of the Science (2022b) indicated median particle sizes ranging from 113 nm to 135 nm and 109 nm to 124 nm by SEM and transmission electron microscopy (TEM), respectively, with up to 44% of particles (by number) being nanoscale.
The NCI (1979) also administered the same dose levels in the diet to male and female B6C3F1 mice for 90 days (highest dose tested was equivalent to 21,500 mg TiO2/kg bw/day [10,000 mg Ti/kg bw/day] in female mice and 16,000 mg TiO2/kg bw/day [13,400 mg Ti/kg bw/day] for male mice, according to EFSA [2016] estimates). No treatment-related adverse effects were observed in either species at any of the doses tested. The NCI (1979) study did not analyze hematological or biochemical parameters in the urine and blood of rats or mice.
In a recent study, Heo et al. (2020) also established a NOAEL of 1,000 mg TiO2/kg bw/day (623 mg Ti/kg bw/day), which was the highest dose tested for agglomerated/aggregated titanium dioxide (P25; particle diameter of agglomerated/aggregated titanium dioxide; P25 was approximately 180 nm) in 28- and 90-day oral toxicity studies in SD rats. Another study by Han et al. (2020) also reported no treatment-related effects on clinical appearance, survival, body weight, feed intake, hematology, clinical chemistry, urinalysis, organ weights, or gross and microscopic pathology in rats administered food-grade titanium dioxide (E171) via gavage at 1,000 mg TiO2/kg bw/day for 90 days. While the authors reported a 6% to 10% increase in feed intake in male rats at 1,000 mg TiO2/kg bw/day, no associated changes in body weight were observed. Authors also reported an 8% decrease in relative lymphocyte counts in low- and high-dose males. Due to the mild effects and inconsistent dose-response, EFSA (2021) considered 1,000 mg TiO2/kg bw/day to be the overall NOAEL from this study.
The potential for inflammation and immunotoxic effects from exposure to titanium dioxide has been investigated in a series of short-term and sub-chronic studies in experimental animals. Riedle et al. (2020) reported no significant differences in inflammation or effects on immune cell populations in the Peyer’s patches of male and female mice (n=6/sex/dose) administered E171 in the diet (particle diameters ranging from 50 nm to 350 nm) at 0, 1, 10, or 100 mg TiO2/kg bw/day for 18 weeks.
In another study, Blevins et al. (2019) examined the immunological effects associated with dietary intake of E171 in rats. In this study, male rats were exposed to E171 (anatase; particle size range of 110 nm to 115 nm, containing 36% nanoscale particles, analyzed by SEM) in a standard diet at a dose of 0, 40, 400, or 5,000 mg/kg diet for 7 days (n=5 animals/dose; dose equivalent to 1.8, 4.8, 31.4, or 374 mg/kg bw/day, respectively) and 100 days (n=15 animals/dose; dose equivalent to 1.3, 3.5, 22.4, or 267 mg/kg bw/day, respectively). Dose conversions were based on the EFSA (2021) assessment. At the start of the study, a separate group of rats (n=5 to 8) was treated with a single intraperitoneal (i.p.) injection of a sterile dose of 180 mg/kg bw dimethylhydrazine (DMH) dihydrochloride as a positive control. The authors did not observe acute or sub-chronic inflammation or effects on the immune system in male rats exposed to E171.
An EOGRT study reported in REACH ([modified 2022]) (described under reproductive and developmental effects) examined developmental immunotoxicity but did not report immunotoxic effects in rats.
Conversely, Bettini et al. (2017) reported immune-suppressive effects in the gut of male rats (n=10) exposed to E171 (anatase; D50 118±53 nm, particle size range of 20 nm to 340 nm, containing 44.7% nanoscale particles, analyzed by TEM) and ultra-sonicated titanium dioxide nano particles (NM-105, particle sizes of 10 nm to 45 nm) in water (using NANOGENOTOX protocol [Jensen et al. 2011]). The animals were exposed to E171, dispersed in water, via intragastric gavage, at 10 mg TiO2/kg bw/day for 7 days. Rats in this series of experiments were used for tissue imaging, flow cytometry, and cytokine assays to investigate tissue inflammation and gut permeability. To study ex vivo immune cell responses, the authors isolated total immune cells from the Peyer’s patches and spleen of untreated rats. These isolated cells were treated ex vivo with E171 and NM-105, before being cultured with anti-CD3/CD28 antibodies to induce cytokine secretion into the culture media. All E171-treated isolated immune cells from Peyer’s patches showed a decrease in T-helper (Th)-1 IFN-γ secretion, while splenic Th1/Th17 inflammatory responses sharply increased. Since these effects were more pronounced in E171-treated cells compared with NM-105-treated, the authors determined that immunosuppression was likely caused by microscale particles. Bettini et al. (2017) also exposed rats to 10 mg TiO2/kg bw/day via drinking water for 100 days. Only animals treated with E171 for 100 days showed microinflammatory effects in the colon. No significant change in paracellular epithelial permeability was observed in the E171-treated rats for 7 or 100 days in comparison with controls. Based on the study results, EFSA (2021) considered E171 to have proinflammatory potential at the systemic level.
Similarly, Han et al. (2020) reported a slight but statistically significant decrease in relative lymphocyte count (~8%) in high- and low-dose males, an approximately 40% decrease in granulocyte-macrophage colony-stimulating factor in females, and alterations in plasma immunoglobulin M (IgM) in both sexes at the highest dose tested, when male and female rats were administered E171 at 10, 100, or 1,000 mg TiO2/kg bw/day via gavage for 90 days. However, EFSA (2021) considered the highest dose tested to be a NOAEL due to the lack of dose-response and natural variability in these parameters.
Studies by Urrutia-Ortega et al. (2016) (dosing at 5 mg TiO2/kg bw/day via gavage for 10 weeks) and Talamini et al. (2019) (dosing of mice at 2 mg TiO2/kg bw/day via drinking water for 3 weeks) reported modest inflammation or immunotoxicity effects in the gut when experimental animals were exposed to E171 at low-dose levels. The results of these studies were considered less reliable, as the studies were not conducted according to a TG and were limited to a single dose level. EFSA (2021) also considered that the modest immunological effects reported in Talamini et al. (2019) could not be identified as adverse because similar effects had been observed in control animals. In addition, the biochemical changes in the stomach and small intestine were considered to be adaptive responses to oxidative stress and not as evidence of adversity. A detailed analysis of immunological effects can also be found in the State of the Science published by Health Canada’s Food and Nutrition Directorate (2022b).
Based on available key reviews and studies (NCI 1979; OECD 2013; Han et al. 2020; REACH [modified 2022]), microscale titanium exhibits low toxicity following short-term and sub-chronic exposure when administered via the oral route. Of note, the studies reporting adverse effects administered titanium dioxide (mainly as E171) either by gavage or through drinking water, whereas none of the dietary studies reported adverse effects in experimental animals.
Reproductive and developmental toxicity
Warheit et al. (2015a) administered titanium dioxide (D50 153 nm to 213 nm) in sterile water at a dose of 0, 100, 300, or 1,000 mg/kg bw/day (0, 62, 187, or 623 mg Ti/kg bw/day, respectively) by oral gavage during gestation days 6 to 20 and days 5 to 19 to SD and Wistar rats (22 animals/dose), respectively. The study design consisted of several TGs, including OECD TG 414 (prenatal developmental toxicity study). Maternal animals were monitored for body weight changes, food consumption, and clinical observations during the experiment. At the end of gestation, dams were euthanized, and the uterine contents were examined, including counts of corpora lutea, implantation sites, resorptions, and live and dead fetuses. Fetuses were examined for sex, body weight, and skeletal malformations. Additionally, fresh visceral and head examinations were performed on selected fetuses. No evidence was found for any treatment-related maternal or developmental effects in any animals at any of the doses tested. The authors concluded that the NOAEL for developmental toxicity of titanium dioxide was 1,000 mg TiO2/kg bw/day (623 mg Ti/kg bw/day), which was the highest dose tested.
An EOGRT study with E171 was conducted according to OECD TG 443 and in compliance with good laboratory practice (GLP). In this study, SD rats were exposed to E171 (anatase; D50 100 nm, 50% of individual particles <100 nm) at a dose of 0, 100, 300, or 1,000 mg TiO2/kg bw/day (0, 62, 187, or 623 mg Ti/kg bw/day, respectively) in the diet (REACH [modified 2022]). The basal diet contained roughly 17 mg Ti/kg feed (range of 11 mg Ti/kg to 31 mg Ti/kg feed), which was estimated to be equivalent to approximately 1.4 mg TiO2/kg bw/day (EFSA 2021). Feed palatability was not altered in animals dosed up to 1,000 mg TiO2/kg bw/day in a previous study (REACH [modified 2022]). Sexually mature male and female rats (parental [F0] generation, 24 rats/dose/sex) were exposed to titanium dioxide in the diet beginning 2 weeks before mating and continuously throughout mating, gestation, and weaning of the pups (F1 generation). The F1 generation received the same dose levels in the diet from weaning until post-natal day (PND) 4 of the F2 generation. At weaning, F1 pups were assigned to satellite groups for reproductive/developmental toxicity testing, developmental neurotoxicity testing, and immunotoxicity testing. F2 pups were exposed to treatment in utero and via milk until termination on PND 4.
Treated F0 generation animals did not exhibit any test article-related effects in the estrous cycle in female animals or the sperm parameters (that is, sperm count, sperm viability, and sperm morphology) or organ weights (that is, epididymides and testicles) of male animals (REACH [modified 2022]). No adverse effects in reproductive performance and no treatment-related effects on development and developmental neurotoxicity were observed in pups from satellite groups of the F1 generation at doses up to 1,000 mg TiO2/kg bw/day. The study authors concluded that the NOAEL for reproductive and developmental toxicity of titanium dioxide was 1,000 mg TiO2/kg bw/day (623 mg Ti/kg bw/day) (REACH [modified 2022]). EFSA (2021) agreed with the authors’ conclusion regarding reproductive and developmental toxicity.
The EOGRT study also examined developmental immunotoxicity. A satellite group of F1 generation male and female rats (10/sex/dose) were pretreated with keyhole limpet hemocyanin (KLH) antigen and exposed to E171 in the diet at 0, 100, 300, or 1,000 mg TiO2/kg bw/day for 10 weeks. Cyclophosphamide (CY), which is a known immunosuppressant, was used as a positive control for the KLH assay. Animals were treated with E171 and CY at different time points; therefore, this study did not include a concurrent control for the CY response. As a result, EFSA (2021) determined that the positive control was not valid; therefore, test sensitivity was not clearly demonstrated in this portion of the study. The spleens of the animals were removed and cut in two. One half was used for histopathology, whereas the other half was used to obtain a cell suspension for the analysis of lymphocyte subpopulations. A single cell suspension was prepared, and lymphocyte subpopulations of T cells, T helper cells, T suppressor/cytotoxic cells, NK cells, and B cells were determined using flow cytometry analysis. It should be noted that flow cytometry analysis of splenic cell suspensions was conducted at separate time points, which could influence staining and quantification.
Treated male rats showed a marginal but statistically significant decrease (9%) in the antigen-induced IgM level at the highest dose tested (1,000 mg TiO2/kg bw/day). Both male and female animals showed no treatment-related effects in hematology, spleen weight, histopathology of lymphoid organs (that is, spleen, thymus, lymph nodes, and bone marrow), total and differential peripheral white blood cells count, and splenic lymphocyte subpopulation in both sexes. While all treated animals showed weak immunogenic response to the antigen, these effects were insufficient to identify T cell-dependent immunotoxic effects of E171 (REACH [modified 2022]). The authors indicated that the immune response was not adversely affected by E171, as shown by the KLH assay. EFSA (2021) disagreed, indicating that it was unable to determine an association between E171 and developmental immunotoxicity.
In contrast to the observations of the EOGRT study, Schroeder and Mitchener (1971) reported a significant reduction in the survival of Long Evans (blue spruce) rat offspring in the second generation of a three-generation reproductive toxicity study. However, the applicability of this study was limited, as the type of titanium compound used was not reported and only a single-dose level was tested.
Based on the available key reviews and studies (EFSA 2021; REACH [modified 2022]), microscale titanium displays low reproductive and developmental toxicity.
Genotoxicity
After reviewing a large body of evidence (summarized below) international assessments—such as IARC (2010), NICNAS (2016), ECHA (2017), EFSA (2016, 2018, 2019a, 2019b), and SCCS (2020)—did not raise any concerns regarding the genotoxic potential of titanium dioxide.
Since the publication of previous assessments, EFSA (2021) has re-evaluated the potential genotoxicity of food-grade titanium dioxide, E171. The genotoxicity studies considered in this re-evaluation include studies conducted on E171 (a mixture of microscale and nanoscale titanium dioxide particles), non-food grade microscale titanium dioxide particles, and non-food grade nanoscale titanium dioxide particles. For this human health assessment of microscale titanium dioxide, genotoxicity studies conducted on microscale titanium dioxide or a mixture of microscale and nanoscale particles, including food-grade and non-food grade titanium dioxide, were considered relevant. A detailed analysis of the genotoxicity of titanium dioxide can also be found in EFSA (2021) and Health Canada Food and Nutrition Directorate’s State of the Science of Titanium Dioxide as a Food Additive (2022b). Relevant studies for this human health assessment are primarily based on EFSA (2021) and Health Canada (2022b) and are summarized below.
In vitro genotoxicity of titanium dioxide
There were no in vitro genotoxicity studies conducted on microscale titanium dioxide particles, but information about DNA damage, as assessed by the comet assay and the micronucleus (MN) test, is available for nanoscale and microscale titanium dioxide particle mixtures.
Proquin et al. (2017), Dorier et al. (2017), Dorier et al. (2019), and Franz et al.(2020) studied DNA damage associated with E171 using the comet assay. For example, Proquin et al. (2017) assessed the acute DNA damage induced by E171 using the comet assay in human colon carcinoma cell line (Caco-2). Cells were exposed to a single, non-cytotoxic concentration of E171 at 0.143 µg/cm2 (with or without co-exposure of azoxymethane [AOM]) for 24 hours. DNA damage was represented by the median tail intensity of the comet. The experiment included a control and hydrogen peroxide (H2O2) positive control. Results showed that E171 induced single-strand DNA breaks, with or without AOM co-exposure. Cell toxicity was not observed during the assay. However, the results of this study are of limited reliability because only a single concentration was tested. Dorier et al. (2017) also reported positive results following repeated exposure (3 weeks) of Caco-2 cell line to 10 or 50 µg/mL of E171. This study is also limited because results were insufficiently reported. Another study by Franz et al.(2020) reported negative results in the comet assay when the colon cancer cell line (HT29-MTX-E12) was exposed to 0, 0.5, 5, or 50 µg/mL of E171 for 48 hours. In a study considered to be highly reliable by EFSA (2021), negative results were reported when Brown et al. (2019) exposed Caco-2 cell line to E171 at concentrations of 3.13, 6.25, 12.5, 25, or 50 μg/ml for 4 hours. Similarly, Dorier et al. (2017, 2019) reported negative results following acute exposure of Caco-2 cell line to E171 at 10 or 50 µg/mL for 6 or 48 hours (2017 study) and at 50 µg/mL for 24 hours (2019 study). It was noted that the studies by Dorier et al. (2017, 2019) had various limitations, including insufficiently reported results and, in the 2019 study, the use of only a single test concentration.
EFSA (2021) also reported mixed results in the comet assay in several studies that used non-food grade forms of titanium dioxide containing a mixture of nanoscale and microscale particles. The results of those studies are summarized below.
DNA strand breaks were also studied using comet assays performed with non-food grade titanium dioxide containing a mixture of nanoscale and microscale particles (Bhattacharya et al. 2009; El Yamani et al. 2017; Andreoli et al. 2018; Vila et al. 2018; Brzicova et al. 2019; Murugadoss et al. 2020; Zijno et al. 2020). Andreoli et al. (2018) reported positive results in a comet assay performed using human peripheral blood mononuclear cells (PBMCs) treated with titanium dioxide of various particle sizes (measured by TEM: anatase/rutile, 45 nm to 262 nm; anatase, 50 nm to 270 nm or rutile, 50 to 3,000 nm) at concentrations of 10, 50, 100, or 200 µg/mL for 24 hours. Study authors reported statistically significant increases in single strand breaks in PBMCs for all forms of titanium dioxide. For both anatase and rutile titanium dioxide, single strand breaks were only statistically significant at the highest dose tested, while statistically significant results for the anatase/rutile mixture were reported at 50 µg/mL and above (Andreoli et al. 2018).
Similarly, El Yamani et al. (2017), Murugadoss et al. (2020), and Zijno et al. (2020) all reported positive results for comet assays performed using titanium dioxide particle sizes ranging from 50 nm to 150 nm. Equivocal results were reported by Vila et al. (2018) and Brzicova et al. (2019) for the same range of particle sizes, whereas Bhattacharya et al. (2009) reported negative results for titanium dioxide particles (50 nm to 150 nm) in the comet assay. EFSA (2021) considered all of the above-mentioned studies using non-food grade titanium dioxide (containing a mixture of nanoscale and microscale particles) to be highly reliable. El Yamani et al. (2017) also performed a comet assay using human lymphoblastoid cells (TK6), in addition to human alveolar carcinoma cells (A549); however, the reliability of this portion of the study is low due to slightly low cell viability.
Proquin et al. (2017) and Franz et al. (2020) conducted in vitro chromosomal aberration/mammalian cell MN tests using E171. Proquin et al. (2017) reported positive results in the MN test when a human colon adenocarcinoma cell line (HCT116) was treated with E171 for 24 hours at concentrations of 50,100, 500, or 1,000 μg/mL. EFSA (2021) assigned limited reliability to this study due to the lack of a positive control and independent replicates. In contrast, Franz et al. (2020) reported negative results in an MN test in the HT29-MTX-E12 cell line following exposure to 0.5, 5, or 50 µg/mL of E171 (170 nm). The E171 suspensions used in this study were intentionally prepared to generate large agglomerates representing the particle size distribution of E171 in the food matrix. The reliability of the negative results in the Franz et al. (2020) study is difficult to interpret, as the agglomeration status of the particles in the exposure media was not confirmed, and the agglomerates themselves interfered with the detection of micronuclei in the flow cytometry-based scoring method used by the authors (Health Canada 2022b). Additionally, the authors did not evaluate the cellular uptake of the particles (Health Canada 2022b). EFSA (2021) also considered this study to be of low reliability due to methodological limitations, including an insufficiently reliable flow cytometry approach. The detection of micronuclei by flow cytometry was impeded by the presence of large titanium dioxide agglomerates intentionally created for the study.
Several other studies conducted using non-food grade titanium dioxide containing both nanoscale and microscale particles reported mixed results (Uboldi et al. 2016; Di Bucchianico et al. 2017; Andreoli et al. 2018; Zijno et al. 2020). Positive MN results were reported by Uboldi et al. (2016) when a Balb/c 3T3 (mouse embryo fibroblasts) cell line was exposed to titanium dioxide (60 nm to 400 nm) at a concentration of 10 µg/mL for 72 hours. EFSA (2021) considered this study to be of limited reliability because it included only a single concentration. However, several other studies, which were rated as highly reliable by EFSA (2021), reported negative results in MN tests for titanium dioxide with mixed nanoscale and microscale particles (Di Bucchianico et al. 2017 [50 nm to 150 nm]; Andreoli et al. 2018 [45 nm to 262 nm]; Zijno et al. 2020 [50 nm to 150 nm]).
In vivo genotoxicity of titanium dioxide
In vivo genotoxicity, as assessed by the comet assay and MN test, are available for both E171 and non-food grade titanium dioxide microscale particles (>100 nm) (EFSA 2016, 2021).
Sycheva et al. (2011) and Murugadoss et al. (2020) reported positive results on comet assays following gavage administration of titanium dioxide. Sycheva et al. (2011) exposed male mice (n=5 per group) to titanium dioxide (anatase; 160±59 nm – measured by electron microscopy) at 40 or 200 mg TiO2/kg bw daily for 7 days and examined the potential of inducing DNA damage in the liver, brain, and bone marrow cells 24 hours after the last treatment. No positive control group was included. A statistically significant increase in mean % tail DNA was observed at both doses in the bone marrow test. No DNA damage was observed in liver or brain cells. EFSA (2016) considered the study to be of limited reliability due to study limitations, including the lack of a positive control and lack of information on organ toxicity. Heath Canada (2022b) discussed several additional limitations, including the lack of dose-response and deviation from OECD TG 489 (for example, the use of only two dose levels, analysis of DNA damage 24 hours after treatment instead of the standard 2 to 6 hours after treatment).
Murugadoss et al. (2020) exposed female mice (n = 4 to 5 per group) to titanium dioxide (anatase; 117 nm – measured using TEM) at 10, 50, or 250 µg TiO2/mouse via oral gavage and evaluated DNA damage in peripheral blood cells. The titanium dioxide suspensions used in the study were composed of either small or large agglomerates with similar dispersion medium composition. Untreated animal blood exposed to 100 μM H2O2 for 15 minutes served as a positive control. Blood samples were collected three days after treatment and analyzed in an alkaline comet assay. Significantly positive results for the comet assay were reported in all three dose groups; however, there was no significant quantitative difference in the DNA damage between mid and high doses. EFSA (2021) considered this study to be of low reliability due to the lack of dose-response. Owing to the limitations of the study protocol, Health Canada’s Food and Nutrition Directorate considered the results of this study to be equivocal (Health Canada 2022b).
In contrast, Bettini et al. (2017) and Jensen et al. (2019) reported negative results for in vivo comet assays conducted using E171. Jensen et al. (2019) administered 50 or 500 mg TiO2/kg bw of E171 [anatase; three size groups of particles: 135, 305, or 900 nm (TEM image)] to rats (10/group) once a week, for10 weeks. At 24 hours after the last dose, liver and lung cells were analyzed for DNA damage using an alkaline comet assay (with or without formamidopyrimidine-DNA glycosylase [Fpg]). Authors reported negative results for DNA damage in lung and liver tissues for all three particle sizes. Although EFSA (2021) considered this study to be highly reliable and relevant, Health Canada’s Food and Nutrition Directorate (2022b) considered the negative results to be difficult to interpret due to several study limitations, including a deviation of the test protocol from the OECD TG 489—for example, the use of only two dose groups, the analysis of DNA damage 24 hours after last exposure instead of 2 to 6 hours after the last dose, and the use of an outdated dosing regime and visual scoring method for DNA damage instead of automated or semi-automated image analysis software. In addition, due to the low bioavailability of titanium dioxide via the GIT, it is unclear whether the systemic exposure is high enough to induce DNA damage in lung and liver tissues. Bettini et al. (2017) also reported negative results for DNA damage when adult male Wistar rats were exposed to 10 mg TiO2/kg bw/day of E171 (anatase; D50 118±53 nm, range of 20 nm to 340 nm, containing 44.7% particles <100 nm, as determined by TEM) via oral gavage for 7 days. No positive control was included in the study. At the end of dosing (time is not specified), cells from the Peyer’s patch were collected for DNA strand breaks using an alkaline comet assay, with or without Fpg. Authors reported negative results for the DNA strand breaks and oxidative DNA damage. The Bettini et al. (2017) study also had several limitations, including deviation of the test protocol from the OECD TG 489 (for example, testing of only a single dose and the lack of a positive control).
Few authors assessed the potential of microscale titanium particles to induce MN using in vivo studies administering titanium dioxide either orally or via i.p. injection (Shelby et al. 1993; Shelby and Witt 1995; Sycheva et al. 2011; Donner et al. 2016). According to the EFSA (2021) analysis, Shelby et al. (1993) and Shelby and Witt (1995) reported equivocal results for the MN test when male mice (n=5) were administered titanium dioxide (Unitane® 0 to 220, >100 nm) via i.p. injection for 3 days. Two experiments were conducted using different dose levels: 1) 250, 500, or 1,000 mg TiO2/kg bw and 2) 500, 1,000, or 1,500 mg TiO2/kg bw. Dimethylbenzanthracene (12.5 mg/kg in corn oil) was used as the positive control. Twenty-four hours after the final dose, bone marrow and peripheral blood erythrocytes were analyzed for MN in the first experiment, and bone marrow erythrocytes were analyzed in the second experiment. Health Canada’s Food and Nutrition Directorate considered the results of this study to be negative because the elevated test results at the 1,000 mg/kg bw/day dose level (that is, 3.50 and 3.60 micronuclei per 1,000 polychromatic erythrocytes [PCEs] for experiments 1 and 2, respectively) were within the range of control data for the same sex and strain reported by the same authors (that is, 1.10 to 3.70 micronuclei per 1,000 PCEs) (Health Canada 2022b). Shelby and Witt (1995) also tested chromosomal aberration in bone marrow after male mice (n= 8 per group) were administered the same form of titanium dioxide used in Shelby et al. (1993). A single i.p. injection was given at 625, 1,250, or 2,500 mg TiO2/kg bw. Bone marrow was harvested 17 or 36 hours after the injection and analyzed for chromosomal aberration. Authors reported negative results for chromosomal aberration; however, the route of administration in these studies is not considered relevant for evaluating oral toxicity. Inconclusive results were reported by Sycheva et al. (2011) in an MN assay in bone marrow when male mice were exposed to a cosmetic-grade titanium dioxide (anatase; 160 nm ± 59.4 nm determined by electron microscopy) through oral gavage at 40, 200, or 1,000 mg/kg bw/day for 7 days. Bone marrow was removed 24 hours after the last administration. EFSA (2021) reported negative results for the bone marrow MN assay. In the study, the forestomach and colon were also removed, and epithelial cells were analyzed for MN. However, the results were not considered relevant because cytotoxicity was reported in these epithelial cells. EFSA (2016) and Health Canada’s Food and Nutrition Directorate (Health Canada 2022b) identified several additional limitations of the study, including deviation from OECD TG 474 due to the use of fewer sample numbers (1,000 immature erythrocytes per animal instead of the recommended 4,000) and the use of an inappropriate statistical test to analyze the results. Another limitation was the lack of a positive control group in the study protocol. As a result, Health Canada’s Food and Nutrition Directorate considered the results of the bone marrow MN assay to be equivocal. Inconclusive results were also reported by Donner et al. (2016) for MN in peripheral blood reticulocytes when male and female SD rats (n=5 per sex/dose) were given a single oral dose of titanium dioxide (anatase; 27% nanoparticles, hydrodynamic diameter of 153 nm, determined by TEM) at 500, 1,000, or 2,000 mg TiO2/kg bw by oral gavage. EFSA (2016) considered this study to be less reliable due to a lack of demonstrable systemic exposure.
EFSA (2021) also assessed other studies, including markers of DNA damage, oxidized DNA bases, ROS generation, epigenetic DNA methylation, and cell transformation (EFSA 2021). After analyzing the body of evidence, EFSA (2021) concluded that “TiO2 particles had the potential to induce DNA strand breaks and chromosomal damage, but not gene mutations.” EFSA (2021) also reported that multiple modes of action may operate in parallel for the genotoxicity of E171. Uncertainties remain about whether a threshold mode of action could be assumed. Similarly, after analyzing the physicochemical properties of titanium dioxide particles, EFSA (2021) stated that a cut-off value for particle size could not be established for genotoxicity. As a result, EFSA (2021) concluded that “a concern for genotoxicity of TiO2 particles that may be present in E171 cannot be ruled out.”
Based on available key reviews (EFSA 2016, 2021),microscale titanium dioxide particles display mixed results for genotoxicity in in vitro and in vivo assays.
The UK independent Government Committee on Mutagenicity (COM) reported that the limitations of the current data used to characterize genotoxicity, such as mixed particle sizes and a wide variety of testing approaches, did not support a definitive conclusion. Therefore, the COM did not agree with the overall conclusions of EFSA (2021) on the genotoxicity of E171 (COT 2022).
Recently, Kirkland et al. (2022) published a comprehensive weight-of-evidence assessment on the genotoxicity of titanium dioxide using available data, including the genotoxicity studies considered by EFSA (2021). The studies that met the reliability and quality criteria included both microscale and nanoscale titanium dioxide particles. Based on the analysis, the authors determined that the studies that reported positive results for genotoxicity were associated with high cytotoxicity, oxidative stress, inflammation, apoptosis, or a combination of all of these effects. The authors of the study also determined that titanium dioxide particle sizes were not correlated with genotoxic effects and that the reproducibility of effects on the same endpoint was not evident from the available studies. As such, the authors acknowledged that the existing evidence does not support a direct DNA damaging mechanism for either nanoscale or microscale titanium dioxide particles (Kirkland et al. 2022).
Carcinogenicity and pre-neoplastic lesions in the GIT
The two-year dietary study by the NCI (1979) examined the carcinogenicity of titanium dioxide. In this study, F344 rats and B6C3F1 mice (50 animals/sex/dose) were fed anatase titanium dioxide (particle sizes ranging from 113 nm to 135 nm and 109 nm to 124 nm, as determined by SEM) in the diet at 0, 25,000, or 50,000 ppm daily for 103 weeks. According to EFSA (2016), these dose levels were equivalent to 2,275 or 4,550 mg TiO2/kg bw/dayfor female rats and 2,025 or 4,050 mg TiO2/kg bw/dayfor male rats. The dose conversions for mice were 5,375 or 10,750 mg TiO2/kg bw/dayfor females and 4,225 or 8,450 mg TiO2/kg bw/dayfor males. Food consumption rates and body weights of adult male and female rats and mice were used to calculate the dose conversion. At 104 weeks, surviving animals were sacrificed, and the gross and microscopic pathology of major tissues, organs, and lesions were evaluated. Although white feces were noted due to the colour of the test material, no treatment-related adverse effects were reported at any dose tested. A significant increase in mortality was observed in female mice exposed to the highest dose; however, this was not considered a treatment-related effect. The significant difference was likely due to a greater survival rate of female mice in the concurrent vehicle control group (Cameron et al. 1985; NSF 2005; Ramoju et al. 2020). The two-year dietary study in mice and rats did not report any significant incidence of tumours in treated animals compared with control animals. The NCI (1979) determined that chronic exposure to titanium dioxide up to 50,000 ppm in the diet was not carcinogenic to Fisher rats or B6C3F1 mice. After analyzing the available data, IARC (2010) concluded that oral, subcutaneous, or i.p. administration of titanium dioxide produced no significant increase in tumour frequency in rats or mice.
EFSA (2021) also investigated the potential for tumour-promoting effects following oral exposure to E171 based on the evidence presented in studies published after the EFSA (2016) scientific opinion.
Bettini et al. (2017) studied the formation of aberrant crypt foci (ACF) in the colon region of rats. It has been suggested that ACF are the earliest pre-neoplastic lesions in colorectal cancer progression. Male rats, pretreated with DMH to induce colon carcinogenesis, were exposed to E171 in drinking water at dose levels of 0 (control animals treated with water only), 200 μg/kg bw/day, and 10 mg/kg bw/day (a human-representative dose) for 100 days. The particle size distribution of E171 ranged from 20 nm to 340 nm (D50 118±53 nm), containing 44.7% particles <100 nm in diameter (Bettini et al. 2017). At the end of the treatment period, animals were randomly sacrificed, and the colons were coded for investigation of aberrant crypts (ABCs) and ACF. The number of ACF and the number of crypts per ACF were counted under a light microscope at 40× magnification in duplicate by two readers. The pathological analysis was conducted in a blinded manner. Based on this data, the authors reported a statistically significant increase in the total number of ABCs per colon, and the number of large ACF per colon (that is, more than three ABCs per ACF) at 10 mg/kg bw/day compared with untreated controls and the 200 μg/kg bw/day groups. The authors also examined whether E171 exposure at 10 mg/kg bw/day would induce spontaneous development of ACF in DMH-untreated rats (n=11). In this portion of the experiment, four E171-treated rats developed lesions with 1 to 3 ABC(s) per ACF, and one rat developed a severe lesion of 12 ABCs. Based on these results, the authors determined that E171 at 10 mg/kg bw/day promoted colon micro-inflammation and spontaneously generated pre-neoplastic lesions in the large intestine. However, Bettini et al. (2017) suggested that the ACF promotional effect is likely due to the nanoscale titanium dioxide particles present in E171 because similar in vitro effects were observed in the same study conducted using nanoscale titanium dioxide particles (that is, NM-105).
The observations of Bettini et al. (2017) could not be replicated in subsequent studies, such as REACH (modified 2022), in which E171 was administered via the oral route. An OECD TG 443-compliant EOGRT study (REACH [modified 2022]) included a satellite group of F0 male and female rats (n=10) to study the potential of ACF formation in the colon from E171 exposure (EFSA 2021). In this portion of the study, rats were exposed to E171 at doses of 0, 100, 300, or 1,000 mg/kg bw/day in the diet over 122 days (study duration reported in REACH [modified 2022]). As ACF examination does not fall within standard methodology, this portion of the study was not a requirement in OECD TG 443. For histopathological analysis, the entire surface of the colon was examined in a blinded manner for ACF and ABCs. Pathology examination was performed in accordance with the OECD TG 443. Mild morphological variability of crypts was observed in seven treated animals, out of the total animals used in the study (males: 1/10, 0/10, 1/10, and 1/10; females: 1/10, 0/10, 1/10, and 2/10 in the control, low-, mid-, and high-dose groups, respectively). However, the authors determined that these changes were inconsistent with the appearance and definition of ACF given in Shwter et al. (2016) (that is, foci containing more than two ABCs). According to this study, oral exposure to E171 at doses up to 1,000 mg/kg bw/day did not induce ACF in the colon. Notably, this study did not include a positive control group with a known tumour initiator, such as DMH, for comparision with ACF formation following E171 treatment. Similarly, Han et al. (2020), who administered sonicated E171 via gavage for 90 days to rats, did not report lesions in the stomach or colon of treated animals.
Blevins et al. (2019) also investigated ACF or ABCs in male rats (n=15) exposed to E171 alone (anatase; 110 nm to 115 nm, 36% nanoscale particles, as analyzed by SEM) via the diet at doses up to 267 mg/kg bw/day for 100 days. However, pathological examination of colon samples was limited to a small area due to a technical issue related to tissue fixation (Blevins et al. 2019). Because of this limitation, EFSA (2021) could not infer the potential for ABC and ACF formation on the basis of this study. A detailed analysis of ACF formation in the GIT and its use as a potential biomarker of colorectal cancer can be found in EFSA (2021) and the State of the Science published by Health Canada’s Food and Nutrition Directorate (2022b).
On the basis of the available key data and reviews (NCI 1979; IARC 2010; OECD 2013; EFSA 2021), the weight of evidence suggests no carcinogenicity concerns associated with oral exposure to titanium dioxide microparticles in experimental animals. EFSA (2021) considered that food-grade titanium dioxide, E171, may induce ACF in male rats based on the findings reported by Bettini et al. (2017), which may indicate a tumour-promoting effect of E171. However, ACF formation associated with titanium dioxide exposure reported by Bettini et al. (2017) was not observed in any other previous or subsequent studies (for example, NCI 1979; Han et al. 2020; REACH [modified 2022]). Health Canada’s Food and Nutrition Directorate also noted that the lack of consistent evidence of pre-neoplastic lesions, including ACF, in the colon of rodents exposed to food-grade titanium dioxide via the oral route (Health Canada 2022b).
Chronic human data
Some epidemiological studies have reported “yellow nail syndrome” resulting from titanium accumulation in the fingernails of individuals chronically exposed to elevated levels of titanium, predominantly from medical interventions (Kim et al. 2019). These studies are of limited use in human health risk assessment, mainly due to insufficient data for establishing a dose-response relationship and insufficient consideration of confounding factors.
Based on the available key data and reviews (NCI 1979; IARC 2010; OECD 2013; EFSA 2021; REACH [modified 2022]), microscale titanium displays low chronic/repeated-dose toxicity in experimental animals and humans.
Selection of critical study and the point of departure for oral exposure to titanium
Previously, international assessments, such as NSF (2005), considered the highest dose tested in the NCI (1979) study to be the critical point of departure (POD) for deriving guidance values. However, since the publication of the NCI (1979) study and the NSF (2005) review, a robust, GLP- and OECD TG-compliant EOGRT study (REACH [modified 2022]) has become available. The EOGRT study examined several key endpoints, including developmental and reproductive effects, developmental neurotoxicity, immunotoxicity, and formation of ACF. A NOAEL of 623 mg Ti/kg bw/day (1,000 mg TiO2/kg bw/day), which is the highest dose tested in the EOGRT study (REACH [modified 2022]), was selected as a suitable POD for risk characterization of oral exposure to microscale forms of the 13 titanium-containing substances in this human health assessment. In the absence of toxicity data on the other titanium-containing substances, the POD from titanium dioxide was used as a surrogate for the group. Several other oral sub-chronic studies in experimental animals exposed to a dose of up to 1,000 mg/kg bw/day titanium dioxide (either pigment-grade or food-grade) also did not indicate adverse effects (Warheit et al. 2015a, 2015b; Han et al. 2020).
5.1.2.1 Derivation of the biomonitoring equivalent
In BE derivation, an internal concentration or range of concentrations of a chemical or its metabolites in a biological medium (for example, blood, urine, or other media) that is consistent with an existing health-based guidance value, such as a RfD or a tolerable daily intake, is derived using available kinetic data or by conducting regression analysis between exposure and blood or urine concentrations (Hays et al. 2008, 2016).
The steady-state titanium whole blood BE for the critical POD from the EOGRT study was derived using the physiologically-based pharmacokinetic (PBPK) model explained in Ramoju et al. (2020). This model was based on a published pharmacokinetic model by Heringa et al. (2016). The Heringa et al. (2016) model was based on kinetic data from Geraets et al. (2014), with the authors assuming that kinetic parameters from i.v. dosing are similar to the parameters of oral exposure. In Geraets et al. (2014), Wistar rats were administered titanium dioxide particles of various sizes intravenously (NM-100, NM-102, NM-103, and NM-104; mean particle sizes ranging from 67 nm to 267 nm, and nominal particle sizes ranging from 15 nm to 220 nm) (injected dose of 5 mg/kg bw) or by oral gavage (NM-101, NM-102, NM-103, and NM-104; mean particle sizes in the range of 38 nm to 186 nm and nominal particle sizes ranging from 7 nm to 25 nm) (males were administered doses of 6.8 to 8.5 mg TiO2/kg bw/day and females, 10.9 to 12.0 mg TiO2/kg bw/day) for five consecutive days. The treatment period was followed by an observation period of up to 90 days. Tissue samples were collected at days 6, 14, 30, and 90 to analyze titanium concentrations in rats exposed to titanium dioxide through i.v. injection. For rats orally exposed to titanium dioxide, tissue analysis was only performed on day 6.
The model was developed using the key findings from the Geraets et al. (2014) study and incorporated the weight of evidence from other animal and human oral studies. These key findings included: 1) 0.02% of titanium was orally absorbed; 2) blood titanium levels were distributed from the blood to tissues over several days (due to the bimodal elimination pattern of titanium from blood), leading to accumulation in various tissues; 3) the highest concentrations of titanium were measured in the liver and spleen; 4) aside from the liver (fecal elimination), very low or negligible elimination occurred via other routes; and 5) at the end of the observational period, 55% to 80% of the total distributed dose was found in the tissues analyzed in the study (that is, blood, liver, spleen, lung, kidney, heart, brain, thymus, and testes/ovaries) (Ramoju et al. 2020). Thus, the multi-compartmental PBPK model consists of compartments specifically for the blood, liver, spleen, and gonads, and a single compartment representing the “rest of the body” (see Appendix C, Figure C-1). Details on the PBPK model are available in Ramoju et al. (2020).
A sensitivity analysis identified the oral absorption rate as the most sensitive model parameter. Oral absorption had a sensitivity coefficient of 1, indicating that the oral absorption rate and estimated titanium accumulation in tissues are directly proportional. Model validation was conducted using the oral exposure data set found in Geraets et al. (2014). Based on the model validation results, it was determined that the model overestimated the concentration of titanium in the liver by a factor of 1.5 to 4, which is within the range of liver concentration values reported in the published literature (Ramoju et al. 2020).
This model facilitates the calculation of internal concentrations (that is, blood and tissue concentrations) of titanium following oral ingestion (Heringa et al. 2016; Ramoju et al. 2020). Therefore, the model was used in the BE derivation to simulate the titanium concentration in whole blood. The model assumed that titanium particles were uniformly distributed across all components in the blood (that is, plasma, erythrocytes, serum) (Heringa et al. 2016; Ramoju et al. 2020).
Ramoju et al. (2020) derived a BE value of 28 µg/L for the RfD established by the NSF (2005), which was based on the NOAEL from the NCI (1979) study and the application of UFs (that is, x10 for interspecies extrapolation, x10 for intraspecies variability, and x10 for database deficiency). The additional UF of 10 for database deficiencyaccounted for the lack of a one-generation reproductive toxicity study.
A new BE for this human health assessment was derived for male and female rats using the NOAEL of 623 mg Ti/kg bw/day, the highest dose tested in the EOGRT study, which became available after the publication of Ramoju et al. (2020) (REACH [modified 2022]). The model code for titanium pharmacokinetics in rats after oral administration was obtained from the supplementary data of Ramoju et al. (2020) to derive a steady-state whole blood BE value. The PBPK model was simulated for the POD for both F0 and F1 generations for chronic steady-state scenarios. The model was run in the Berkeley Madonna platform, using a starting age of 71 days for the F0 generation and 21 days for the F1 generation. The starting age is essential to ensure the model estimates accounts for food consumption increasing with age. According to the model simulation for chronic exposure, the approximate steady-state blood concentrations of titanium associated with the NOAEL (BEPOD) for male and female rats were 2.15 and 1.61 mg/L, respectively. Following the application of UFs of 2.5 for interspecies toxicodynamic variation and 10 for intraspecies variation, the BE values for male and female rats were 86 and 65 µg/L, respectively. The UF for interspecies toxicokinetic variation was not considered, as it was already accounted for in the PBPK model. As a conservative approach, the lowest BE of 65 µg/L for female rats was brought forward for risk characterization of systemic exposure. The BE derivation steps are presented in Table C-1 of Appendix C.
The EOGRT study also analyzed blood concentrations associated with each dose level, and a summary of the data are available in the EFSA (2021) report. According to the study, the F0 animals did not show a clear increase in blood titanium concentrations with increasing dose levels. However, the animals in the F2 generation showed a dose-dependent increase in titanium concentrations. The median blood titanium concentrations for exposed animals ranged from 0.01 µg/g to 0.542 µg/g, which is equivalent to 10 µg/L to 542 µg/L, assuming that the density of blood is 1 g/L (EFSA 2021). While the measured blood concentration at the lower end is below the blood concentrations derived from the PBPK model (that is, BEPOD), the reported blood concentration for the upper end is within the same order of magnitude of the concentrations derived from the PBPK model. EFSA (2021) considered that uncertainties remained in the measured blood concentrations due to considerable variability in background concentrations and the magnitude of the estimated method limits of detection and limit of quantifications. In addition, the blood concentrations reported by EFSA (2021) do not contain data for the F1 generation. Due to these limitations, the BE values derived from the PBPK model will be used for the risk characterization of oral exposure to titanium-containing substances in this assessment.
5.1.3 Health effects of dermal exposure to titanium
Based on available data and reviews, titanium dioxide poses low acute, short-term, and chronic toxicity via the dermal route of exposure because microscale titanium dioxide cannot penetrate beyond the outermost layer of viable skin (NCI 1979; Sadrieh et al. 2010; OECD 2013; NICNAS 2016).
Several carcinogenicity studies are available on rats and mice exposed to titanium dioxide via the dermal route (CLH 2016). These studies reported negative results for carcinogenicity; however, because they were conducted using nanoscale titanium dioxide particles (CLH 2016), they were not considered further in this human health assessment.
Based on available key reviews and studies (Sadrieh et al. 2010; CLH 2016; ECHA 2017), titanium displays no adverse effects via the dermal route of exposure due to low dermal absorption of the substance.
5.1.4 Health effects of inhalation exposure to titanium
In the absence of inhalation toxicity data for most of the titanium-containing substances in this group, inhalation toxicity data for titanium dioxide was used as surrogate data for the health effects assessment of the Titanium-containing Substances Group.
Acute exposure
A limit test conducted according to OECD TG 403, cited in REACH ([modified 2022]), was available to assess acute inhalation exposure to titanium dioxide. Male and female SD rats (5/sex/dose) were exposed by nose-only inhalation for 4 hours to titanium dioxide, at measured concentrations of either 3.43 mg/L (3,430 mg TiO2/m3) (MMAD 3.2 µm) or 5.09 mg/L (5,090 mg TiO2/m3) (MMAD 7 µm). The animals were monitored for 14 days. Over the 14-day post-exposure observation period, no mortality, body weight changes, or adverse clinical signs were reported for any of the exposure concentrations.
Based on available key data (REACH [modified 2022]), titanium displays low acute toxicity via the inhalation route.
Short-term toxicity
In a study conducted by Warheit et al. (1997), CD male rats were administered titanium dioxide dust via whole-body inhalation for 6 hours/day, 5 days/week, for 4 weeks at 5, 50, or 250 mg TiO2/m3 (MMADs of 1.9, 1.7, or 1.4 µm, respectively) and observed for 6 months post-exposure. Animals were evaluated by bronchoalveolar lavage fluid (BALF) analysis, clearance analysis, in vitro macrophage function, and histopathology at 0 hour, 1 week, and 1-, 3-, and 6-month post-exposure. The mid- and high-dose animals showed a wide spectrum of effects within the lungs, and although the types of lesions were similar at both doses, the severity was significantly higher at the highest dose. Exposure to 250 mg TiO2/m3 for 4 weeks produced a persistent inflammation and macrophage aggregation, which was sustained throughout a 3-month post-exposure period and remained visible at 6 months post-exposure. No effects were reported at 5 mg TiO2/m3; therefore, this dose is considered to be the no-observed-adverse-effectconcentration (NOAEC).
In another study by Henderson et al. (1995), as cited in NIOSH (2011) and OECD (2013), female rats were exposed to titanium dioxide (rutile; MMAD 1.3 μm) via nose-only inhalation at concentrations of 0, 0.1, 1.0, or 10 mg TiO2/m3 for 6 hours/day, 5 days/week for 4 weeks, followed by a 24-week observation period. There were no changes in the BALF or any histopathological changes. Therefore, the OECD (2013) established the NOAEC at 10 mg TiO2/m3 (6.0 mg Ti/ m3).
Bermudez et al. (2002) examined the effects of inhaled rutile titanium dioxide (MMAD 1.4 µm) in female rats, mice, and hamsters in a 13-week study. Animals (65, 73, and 73 animals/dose for rats, mice, and hamsters, respectively) were exposed to 0, 10, 50, or 250 mg TiO2/m3 pigmentary titanium dioxide via whole-body inhalation for 6 hours/day, 5 days/week over 13 weeks, with recovery groups held for an additional 4, 13, 26, or 52 weeks (46 weeks for hamster study), respectively, post-exposure. At each point, animals were studied for lung burden and a variety of pulmonary parameters, including inflammation, cytotoxicity, lung cell proliferation, and histopathological alterations. Both rats and mice showed significant impairment in alveolar macrophage-mediated clearance at exposure levels of 50 and 250 mg TiO2/m3, resulting in pulmonary overload. Hamsters were able to clear titanium dioxide particles more effectively than the other two species. Inflammation, as indicated by an increase in macrophage, neutrophil, total protein, and lactate dehydrogenase in BALF, was reported at 50 and 250 mg/m3 in all three species. In hamsters, inflammation markers were significantly elevated only at the highest dose level compared to control animals (Bermudez et al. 2002). Inflammation was more severe in rats than in mice and hamsters. In mice and rats, inflammation was observed throughout the post-exposure recovery period, whereas in hamsters, inflammation eventually disappeared due to rapid clearance. Histopathological observation showed alveolar hypertrophy and hyperplasia in Type II epithelial cells at 50 and 250 mg/m3 in rats after 13 weeks of exposure. At 250 mg TiO2/m3, rats also showed alveolar metaplasia, which was not seen in mice or hamsters. Observation of alveolar hypertrophy and hyperplasia in Type II epithelial cells was minimal in hamsters. The OECD (2013) considered the NOAEC in this study to be 10 mg TiO2/m3 (6.0 mg Ti/m3) for all species tested.
Other authors, such as Everitt et al. (2000) and Reverdy et al. (2000), also reported similar findings to Bermudez et al. (2002) when rats, mice, and hamsters were exposed to the same dose levels of titanium dioxide microparticles for 13 weeks.
In another study, Thyssen et al. (1978) exposed male and female rats (50/sex) to 16 mg TiO2/m3 (0.5 µm) for 6 hours/day, 5 days/week for 12 weeks, with animals observed until spontaneous death. Exposed animals did not show any treatment-related change in clinical observations, body weight, or carcinogenicity (Thyssen et al. 1978).
Genotoxicity
Based on the decision of EFSA (2016) and ECHA (2017) and an analysis of available studies, the SCCS (2020) determined that, if exposure occurs through inhalation, titanium dioxide could exert genotoxic effects in the lungs. The genotoxicity is likely due to indirect mechanisms, such as oxidative stress or secondary mechanisms resulting from chronic alveolar inflammation caused by impaired macrophages following the development of lung overload (Driscoll et al. 1997; CLH 2016; SCCS 2020). Thus, lung overload would be required prior to the development of genotoxicity. This mechanism of action is associated with any type of small particle, rather than a particular characteristic of titanium.
Chronic toxicity and carcinogenicity
In 2006, the IARC concluded that, for titanium dioxide, there was sufficient evidence of carcinogenicity via the inhalation route in experimental animals and inadequate evidence of carcinogenicity in humans (Group 2B – “possibly carcinogenic to humans”) (CAS RNs 13463-67-7, 1317-70-0, and 1317-80-2) (IARC 2010). The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has classified the respirable fraction of titanium dioxide as a category 4 carcinogen (Hartwig 2020).
The IARC (2010) considered that the classifications apply to both nanoscale and microscale titanium dioxide particles. The supporting studies for the carcinogenicity classifications are summarized below. It should be noted that lung tumours were only reported at dose levels that caused lung overload in inhalation animal bioassays for titanium dioxide. Additionally, the exposure levels at which the tumours were reported in the microscale titanium dioxide study (Lee et al. 1985) exceeded the maximum tolerable dose. In contrast to the IARC (2010) classification, the National Industrial Chemicals Notification and Assessment Scheme of Australia (NICNAS) recommended that the substance does not require classification and labelling (NICNAS 2016). The NICNAS (2016) conclusion was based on several criteria, including the implementation of sufficient ongoing risk management measures, lack of genotoxicity, and observation of lung overload in rats prior to tumour development.
The carcinogenicity classifications for titanium dioxide were based on three chronic inhalation studies in animals using microscale titanium dioxide (Lee et al. 1985 and Muhle et al. 1991) and nanoscale particles (Heinrich et al. 1995). In addition, epidemiological studies were reviewed by the IARC (2010) and NIOSH (2011) , and adequate evidence for carcinogenicity in humans was not found. The key animal studies are summarized below.
Lee et al. (1985) exposed groups of male and female Crl:CD rats (50 animals/sex/dose) via inhalation to a rutile titanium dioxide (MMAD 1.5 µm to 1.7 µm) at concentrations of 0, 10, 50, or 250 mg TiO2/m3 using whole-body inhalation for 6 hours/day, 5 days/week over 2 years. None of the exposed groups showed treatment-related abnormal clinical signs, body weight changes, or excess of morbidity or mortality compared with the untreated control group. Increased incidences of pneumonia, tracheitis, and rhinitis with squamous metaplasia of the anterior nasal cavity were reported in both males and females in all treatment groups. The severity of the lesions was dose-dependent and minimal at 10 mg TiO2/m3. The authors determined that the effects at 10 mg TiO2/m3 met the biological criteria for a “nuisance dust” and that those effects were mild and reversible. At doses of 50 mg TiO2/m3 and higher, there was a significant increase in lung and thymus weights. Animals in these treatment groups also showed alveolar proteinosis, bronchiolarization of alveoli, and fibrosis. While no significant increase in lung tumours was reported at 10 or 50 mg TiO2/m3, bronchioalveolar adenomas (benign lung tumours) were reported in both sexes at 250 mg TiO2/m3. These tumours were considered secondary to lung overload in the test animals and are not specific to titanium exposures below this threshold (NICNAS 2016; Thompson et al. 2016; ECHA 2017). Animals also showed non-neoplastic cysts. No carcinomas were reported in this study. Based on the treatment-related lung effects (that is, tracheitis, rhinitis with squamous metaplasia of the anterior nasal cavity, alveolar cell hyperplasia, and broncho/bronchiolar pneumonia), 10 mg TiO2/m3 (6.0 mg Ti/m3) is considered to be the lowest-observed-adverse-effect concentration (LOAEC).
Muhle et al. (1991) administered titanium dioxide (MMAD 1.1 µm) via whole-body inhalation to rats (50 rats/sex/dose) at 0 or 5 mg TiO2/m3 for 6 hours/day, 5 days/week for 24 months. No significant difference in lung tumours was observed in exposed animals. A 5% incidence of lung fibrosis, minor changes in the cytologic pattern of BALF, and lymphoid hyperplasia of lung-associated lymph nodes were noted in exposed animals. However, this study was designed to test only a single concentration of titanium dioxide as a positive control for a study testing carcinogenicity of inhalation exposure to toner. As only a single concentration was tested, and the study design did not follow any TGs, this study was not considered sufficiently robust to derive a critical POD for chronic exposure to titanium.
Another study considered by the IARC (2010) was a chronic rat and mice study conducted by Heinrich et al. (1995) using ultrafine (nanoscale) titanium dioxide particles. While studies conducted on nanoparticles are not relevant to this human health assessment, the details of this study are included here because it is one of the key lines of evidence used by IARC (2010) for its cancer classification. The female Wistar rats and female Crl:NMRI BR mice (100 animals/dose) were exposed by whole-body inhalation to TiO2 (primary particle sizes of 15 nm to 40 nm) at an average air concentration of 10 mg TiO2/m3 for 18 hours/day, 5 days/week (for both species, as cited in NIOSH 2011) over 24 and 13.5 months, respectively. Following cessation of dosing, animals were maintained in clean air for recovery (6-month period for rats and 9.5-month period for mice). Benign keratinizing cystic squamous-cell tumours, adenoma, adenocarcinomas, and squamous cell carcinomas were observed at 10 mg/m3 in exposed rats. The total number of lung tumours differed significantly in exposed rats compared with control animals. However, mice did not show a significantly increased incidence of lung tumours. Since only a single concentration of titanium dioxide nanoparticles was used, this study was not considered further in this human health assessment. It should also be noted that studies have shown that ultrafine (nanoscale) particles produce more severe pulmonary effects in rats, including lung carcinomas, than an equal mass of microscale particles (NIOSH 2011; Thompson et al. 2016; ECHA 2017).
Rats exposed to concentrations of 50 mg TiO2/m3 and above in Lee et al. (1985) showed impaired lung clearance pathways due to pulmonary overload (Warheit and Frame 2006; IARC 2010; NIOSH 2011; NICNAS 2016; ECHA 2017; Kawasaki 2017). Other authors have concluded that the rat model is more sensitive to titanium dioxide-induced lung effects than other rodent models, including mice and hamsters and non-human primate models (monkeys) (Krombach et al. 1997; Bermudez et al. 2002; Warheit and Frame 2006). Thus, the lung tumours reported in rats exposed to high concentrations of titanium dioxide microscale particles in Lee et al. (1985) were not considered to be relevant specifically for exposure of the general population to titanium, as tumours only occurred at concentrations that caused lung overload (that is, ≥250 mg TiO2/m3) (Warheit and Frame 2006; NIOSH 2011; Kawasaki 2017). This is consistent with the ECHA (2017) opinion on the proposed harmonized classification and labelling of TiO2. The report states that complete cessation of alveolar clearance occurred at 50 mg TiO2/m3 and above in Lee et al. (1985), which is consistent with an observation of pulmonary overload (ECHA 2017). A similar outcome was reached in a comprehensive review by Thompson et al. (2016). The authors agreed that particle overload is a well-accepted concept for fine (microscale) titanium dioxide particles. The authors further explained that the mechanism of toxicity induced by ultrafine (nanoscale) particles is not well understood (Thompson et al. 2016).
A recent review by Bevan et al. (2018) explored the issue of lung overload and lung cancer associated with toxicity testing of poorly soluble particles, such as titanium dioxide, carbon black, talc, and toner particles in rodents. They determined that, while the evidence suggests that the rat lung model is unreliable as a predictor for human lung cancer risk associated with these substances, it is a sensitive model for detecting various threshold inflammatory markers and may useful for non-neoplastic risk assessment. A similar conclusion was reached by Warheit et al. (2016) and is consistent with that outlined in ECETOC (2013).
Thus, the inflammatory response noted in animals at 10 mg TiO2/m3 (6.0 mg Ti/m3) in Lee et al. (1985) was considered to be the critical effect for chronic risk characterization. The titanium dioxide concentration at the LOAEC (that is, 10 mg TiO2/m3) was converted to a titanium concentration using the molecular weights of titanium and titanium dioxide (10 mg TiO2/m3 × [47.87 g/mol / 79.87 g/mol] = 6.0 mg Ti/m3) to be applicable to all titanium-containing substances in the group. The LOAEC of 6.0 mg Ti/m3 was derived from a study in which animals were exposed on an intermittent basis (6 hours/day, 5 days/week). The LOAEC of 6.0 mg Ti/m3 was further adjusted to represent the continuous exposure concentration by multiplying the number of hours per day (6/24) and the number of days per week (5/7) that titanium dioxide was administered to test animals. This adjustment was made according to the United States Environmental Protection Agency (US EPA) guidance on inhalation risk assessment (US EPA 1994, 2009). The adjusted LOAEC for non-cancer effects is 1.1 mg Ti/m3. This adjustment is considered appropriate when available toxicokinetic data indicate that titanium particles deposited in the lungs can accumulate over time due to slow clearance, which could lead to time-related enhanced lung effects.
Human data
Several epidemiological studies reported a correlation between environmental titanium exposure during pregnancy and low birth weight (Bell et al. 2012; Basu et al. 2014; Jin et al. 2021). However, these effects were reported at air concentrations several-fold higher than the average exposure levels from air concentrations reported for the general population.
Epidemiology studies that examined titanium dioxide inhalation exposure in occupational settings have shown no clear evidence of lung overload or carcinogenicity in workers (IARC 2010; NIOSH 2011; ECETOC 2013; ECHA 2017). Although several international agencies, such as OSHA (2002), ACGIH (2009), and NIOSH (2011), have derived exposure guidance values for workers, no such guidance values have been developed for titanium dioxide inhalation exposure in the general population.
These epidemiological studies were limited by various shortcomings, such as small sample sizes, imprecise or absent exposure assessment, and insufficient consideration of confounding factors. As a result, the critical POD for this human health assessment was not based on available epidemiological studies, although they were used as supporting evidence for the health effects assessment.
Summary of hazard data for inhalation exposure
In the absence of inhalation toxicity data for most of the titanium-containing substances in the group, inhalation toxicity data for titanium dioxide was used as surrogate data for the health effects assessment of the group.
Overall, microscale titanium (as titanium dioxide) inhalation has been shown to produce portal-of-entry (lung tissue) effects in all species tested. In animal models (specifically the rat), failure to clear titanium dioxide particles from the lung leads to lung overload and subsequent cancer development (Bevan et al. 2018). In human studies, lung lesions are limited to inflammatory reactions or fibrosis (Bos et al. 2019). As the lung tumours noted in rats occur only at doses that cause lung overload (Lee et al. 1985), lung carcinogenicity associated with titanium dioxide exposure is not considered relevant to humans exposed to much lower concentrations. Several other authors also reached similar conclusions (Warheit and Frame 2006; ECETOC 2013; Bevan et al. 2018).
The LOAEC of 10 mg TiO2/m3 (6.0 mg Ti/m3), based on treatment-related lung effects in rats reported by Lee et al. (1985), was selected as the critical POD. These lung effects included tracheitis, rhinitis with squamous metaplasia of the anterior nasal cavity, alveolar cell hyperplasia, and broncho/bronchiolar pneumonia. For the risk characterization of chronic inhalation exposure to titanium-containing substances in the general population, a continuous air concentration for titanium (that is, 1.1 mg Ti/m3) was calculated using the critical POD.
5.1.5 Consideration of subpopulations who may have greater susceptibility
There are groups of individuals within the Canadian population who, due to greater susceptibility, may be more vulnerable to experiencing adverse health effects from exposure to substances. The health effects assessment took into consideration the potential for differences or increased susceptibility based on life stage (that is, the developing fetus), age, and sex. The available data for titanium consist of kinetic, acute, short-term, sub-chronic, chronic, reproductive and developmental, neurodevelopmental, immunotoxicity, genotoxicity, and carcinogenicity data in experimental animals. The data used to characterize risk also include epidemiological data from workers and pregnant women. The available kinetic and health effects data do not indicate any difference in kinetic parameters or susceptibility to titanium-induced health effects based on life stage, age, or sex. These considerations were taken into account in the selection of the critical health effect for risk characterization.
5.2 Exposure assessment
Numerous studies have measured titanium in various media, including blood, air, drinking water, soil, dust, and products available to consumers. These studies provide concentrations of total titanium in these media but not substance-specific concentration data. In this exposure assessment, total titanium data will be used as a surrogate for substance-specific exposure data. Data on total titanium are expected to be a conservative surrogate for the 13 titanium-containing substances considered in this assessment, since total titanium data for environmental media, food, drinking water, and products would include naturally occurring titanium and contributions from titanium-containing substances beyond the 13 substances in this Group.
This exposure assessment focuses on the characterization of exposure to the microscale form of substances in the Titanium-containing Substances Group. Nanomaterials containing titanium (particle sizes of 1 nm to 100 nm) that may be present in environmental media or products are not explicitly considered in the exposure scenarios of this assessment, but measured concentrations of total titanium in environmental media, food, or human biomonitoring data could include titanium from these sources.
Titanium and its alloys are used in medical procedures, such as dental implants and hip replacements. The health effects related to these uses were not considered in this assessment.
5.2.1 Environmental media, food, and drinking water
Titanium is a naturally occurring element present in environmental media in Canada (Grunsky et al. 2012; NAPS 2015, 2016, 2017, 2018; Rasmussen et al. 2018; WBEA 2019, 2020; CFIA 2020, [modified 2022]; personal communication, email from the Water and Air Quality Bureau [WAQB], Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced). Total titanium has been measured in drinking water distribution systems, soil, outdoor air, indoor air, personal air, household dust in Canada, and infant formula (Appendix A, Table A-2).
Food is a major contributing source of exposure to titanium infor the general population (Jin and Berlin 2015; Ramoju et al. 2020). Titanium is naturally occurring in the environment and thus may enter the food chain; however, it may also be present in foods through the use of titanium-containing food additives, in particular titanium dioxide, and from the potential use of substances in the Titanium-containing Substances Group as components in the manufacture of food packaging materials (personal communication, email from the FND, Health Canada, to the ESRAB, Health Canada, dated March 13, 2018; unreferenced; Health Canada [modified 2024]).
Concentrations of titanium in food were not analyzed as part of Health Canada’s Total Diet Study; however, Canadian occurrence data are available through various surveys conducted by the Canadian Food Inspection Agency (CFIA 2020, [modified 2022]).Footnote 7
Canadian survey results indicate that titanium is found in a wide variety of foods. Titanium concentrations in most foods are less than 0.5 ppm. Some samples of certain foods, such as confectionery, gelatin products, baked goods, and baking mixes, were found to contain higher concentrations of titanium. These foods contained titanium concentrations up to 25 ppm and are permitted to contain titanium-containing food additives. Other foods that reported higher concentrations of titanium were dried foods (for example, spices, dried teas, and baking powder); this is not unexpected, given that titanium would be concentrated during the drying process.
Occurrence data from Europe and the United States (US) were also available for comparison. The highest concentrations of titanium dioxide in foods in Europe, from its use as a food additive, were reported in chewing gum (mean of 3,115 ppm), food supplements in solid, liquid, or chewable form (mean of 14,438 ppm), and processed nuts (mean of 3,775 ppm) (EFSA 2021). In a study of 89 foods purchased from grocery stores in the US, the highest concentrations of titanium per serving were detected in baking ingredients (up to 3,590 ppm), candies (up to 2,080 ppm), chewing gum (up to 2,640 ppm), chocolate (1,250 ppm), products with white icing or powdered sugar topping (up to 2,420 ppm), and powdered products mixed into foods such as drink mixes (up to 1,690 ppm) (Weir et al. 2012).
Typical dietary intake of titanium ranged from 0.3 mg/day to 0.5 mg/day based on data in publications from 1963 to 1969 (Jin and Berlin 2015). More recently, dietary exposure to food-grade titanium dioxide was estimated by EFSA in their 2021 re-evaluation of titanium dioxide (E171) as a food additive (EFSA 2021). The EFSA (2021) assessment was based on consumption data from 40 dietary surveys conducted in 23 European countries, as well as on data on mean food additive use levels in foods reported by industry (mean concentration of E171 in food) and European member states (“refined non-brand-loyal consumer scenario”), most of which were collected during an EFSA call for data in 2013 (EFSA 2013). The upper mean estimated dietary intake of E171 in the refined non-brand-loyal consumer scenario ranged from 2.8 mg TiO2/kg bw/day (1.7 mg Ti/kg bw/day) in older adults over 65 years old to 6.9 mg TiO2/kg bw/day (4.1 mg Ti/kg bw/day) in children 3 to 9 years old (EFSA 2021).
Dietary exposure to E171 was also modelled for the US population using intake data from the national diet and nutrition survey in the UK and titanium concentrations in foods from the UK and the US (Weir et al. 2012). Average daily intake of E171 was estimated to range from 1 mg TiO2/ kg bw/day to 2 mg TiO2/ kg bw/day (0.6 mg TiO2/ kg bw/day to 1.2 mg Ti/kg bw/day) for children under 10 years old and from 0.2 mg TiO2/ kg bw/day to 0.7 mg TiO2/kg bw/day (0.1 mg TiO2/ kg bw/day to 0.4 mg Ti/kg bw/day) for other age groups in the US (Weir et al. 2012). In the same publication, average daily intake of E171 in the UK was estimated to range from 2 mg TiO2/ kg bw/day to 3 mg TiO2/kg bw/day (1.2 mg TiO2/ kg bw/day to 1.8 mg Ti/kg bw/day) for children under 10 years old and 1 mg TiO2/kg bw/day (0.6 mg Ti/kg bw/day) for other age groups.
Titanium dioxide is permitted for use in Canada as a food additive in a variety of foods at levels consistent with Good Manufacturing Practice. The foods and levels of use in which titanium dioxide is permitted as a food additive in Canada were similar to the permitted food additive uses in Europe prior to the European Commission’s removal in 2022 of the authorization to use titanium dioxide (E171) in foods in Europe (EC 2022b). Further details on the use of titanium dioxide as a food additive in Canada can be found in the Health Canada Food and Nutrition Directorate’s State of the Science on Titanium Dioxide (Health Canada 2022b). Although some foods that may contain low levels of titanium from its presence in the environment were not included in the EFSA (2021) assessment, monitoring data for foods sold in Canada indicate lower levels of titanium than those reported in the EFSA (2021) assessment. Therefore, exposure estimates for titanium dioxide reported by EFSA are suitable as approximate estimates of potential dietary exposures for the general Canadian population. Upper mean exposure estimates of dietary intakes of E171 from the refined non-brand-loyal consumer scenario generated by EFSA are used as representative dietary intakes for titanium in the Canadian general population (Appendix A, Table A‑3).
Concentrations of titanium in traditional, subsistence, or country foods and surface water consumed by certain Indigenous peoples were measured as part of the Eastern Athabasca Regional Monitoring Program (EARMP), an environmental monitoring program in Northern Saskatchewan (EARMP 2021a, [modified 2021b]). Concentrations of titanium in fish, mammals, birds, and berries were measured in six communities in Northern Saskatchewan from 2011 to 2020. Data measured in samples from 2015 to 2020 were combined to generate representative concentrations (that is, average or 95% upper confidence level of the mean [UCLM]) in each food commodity, using the approach presented in the EARMP human health risk assessment published in 2018 (CanNorth 2018). Concentrations of titanium ranged from 0.01 μg/g in the flesh of lake whitefish in Camsell Portage to 1.2 μg/g in berries (bog cranberries and blueberries) in Stony Rapids (EARMP [modified 2021b]). Intake of titanium from the consumption of country foods in these six communities ranged from 5.5 × 10-5 mg/kg bw/day for adults in Camsell Portage to 2.4 × 10-3 mg/kg bw/day for 1-year-old children in Stony Rapids (Appendix A, Table A‑4). The estimated intake of titanium from the consumption of country foods is not representative of total daily dietary intake, as it does not include contributions from supermarket foods that may be consumed daily by individuals in these communities. The highest estimated intake of 2.4 × 10-3 mg Ti/kg bw/day for 1-year-old children in Stony Rapids is lower than the highest daily dietary intake of 4.1 mg/kg bw/day for the general Canadian population (Appendix A, Table A‑3). Additionally, biomonitoring data from a study of pregnant women from Northern Saskatchewan are presented in Section 5.2.3, which included a number of the communities sampled in the EARMP (Saskatchewan Ministry of Health 2019).
Titanium was measured in infant formula in Canada as part of the CFIA’s 2018 to 2019 Children’s Food Project (CFIA 2020). Concentrations of titanium were measured in 52 samples of powdered dairy-based infant formula and 7 samples of powdered soy-based infant formulas purchased in the Ottawa, Ontario, and Gatineau, Québec regions of Canada (CFIA 2020). The mean concentrations measured in powdered dairy-based infant formula and soy-based infant formulas were 3.0 × 10-1 and 3.2 × 10-1 mg Ti/kg, respectively (CFIA 2020). Assuming that 9 g of dry formula is reconstituted with 60 mL of water, the mean concentrations of prepared dairy-based infant formula and soy-based infant formulas were 4.5 × 10-5 and 4.8 × 10-5 mg/mL, respectively (CFIA 2020; Mead Johnson & Company, LLC 2020a, 2020b). Assuming that formula-fed infants 0 to 5 months old consume 826 mL of prepared infant formula per day, the average daily exposure to titanium from infant formula for this age group is estimated to be 6.3 × 10-3 mg Ti/kg bw/day (Health Canada 2018). The estimated average exposure to titanium from infant formula for formula-fed infants 6 to 11 months old is 4.0 × 10-3 mg/kg bw/day, assuming that 764 mL of prepared infant formula is consumed per day (Health Canada 2018) (Appendix A, Table A‑5). The highest estimated intake of titanium by formula-fed infants, that is, 6.3 × 10-3 mg/kg bw/day for infants 0 to 5 months old, is lower than the highest estimated dietary intake of 4.1 mg/kg bw/day for children 4 to 8 years old.
No data on titanium concentrations in Canadian human milk were available from the Maternal Infant Research on Environmental Chemicals project or other sources; therefore, occurrence data on titanium in human milk were obtained from the scientific literature. Average concentrations of titanium in human milk were reported in studies conducted in the US, Austria, Ukraine, Poland, Czech Republic, and Germany (Anderson 1992; Amarasiriwardena et al. 1997; Krachler et al. 2000; Wappelhorst et al. 2002; de Rezende Pinto and Almeida 2018). The arithmetic mean concentration of titanium in human milk from studies in the US was 2.40 × 10-4 mg Ti/mL (Anderson 1992; Amarasiriwardena et al. 1997). The arithmetic mean concentration from available studies conducted in the US was used to estimate exposure to titanium from human milk in Canada, as this value was considered the most representative. Assuming that exclusively human milk-fed infants 0 to 5 months old consume 744 mL of human milk per day, average exposure to titanium from human milk was estimated to be 2.8 × 10-2 mg/kg bw/day (Appendix A, Table A‑5).
Titanium may be present in drinking water in Canada from natural and anthropogenic sources. Internationally, titanium concentrations in drinking water are generally low, between 5.0 × 10-4 mg/L and 1.5 × 10-2 mg/L (IPCS 1982). In Canada, there is no health-based drinking water guideline or aesthetic objective for titanium. Canadian drinking water was analyzed for titanium in a national drinking water survey (Tugulea 2016). Titanium was not detected at or above the detection limit of 5.0 × 10-3 mg/L in all samples from distribution systems (n=97) (Tugulea 2016). As a conservative assumption for estimating daily intake, the concentration of titanium in drinking water in Canada is assumed to be equal to the limit of detection from the national drinking water survey data, that is, 5.0 × 10-3 mg/L (Appendix A, Table A‑5).
Concentrations of titanium in soil throughout Canada are expected to vary according to geology and anthropogenic inputs. Average concentration of titanium in soil globally is 0.33 weight percent (Woodruff et al. 2017). The percentage of titanium by weight in soil in the US ranges from 0.007% to 2%, with an average of 0.29%. Titanium concentrations from 483 soil samples collected across Ontario in 1991 ranged from 758 mg/kg to 7,420 mg/kg, with a median concentration of 3,070 mg/kg (Ontario [modified 2015]). The median titanium concentration in Ontario is within the range reported across the US. Due to atmosphere fallout, soil in areas near industrial facilities and point sources of titanium release may be elevated compared with median national levels (IPCS 1982; Woodruff et al. 2017). The median titanium concentration in Ontario of 3,070 mg/kg is used to estimate daily intake from environmental media (Appendix A, Table A‑5).
Titanium was measured in studies of indoor air, outdoor air, personal air, and household dust. Airborne titanium in particulate matter (PM) can originate from natural and anthropogenic sources. In 2015, total titanium was measured in 969 samples from 15 different sites across Canada as part of the National Air Pollution Surveillance (NAPS) Program. The median concentration of titanium particles with an aerodynamic diameter of less than or equal to 2.5 μm (PM2.5) in outdoor air was 8.7 × 10-7 mg/m3 (NAPS 2015). The median concentration of titanium in ambient air measured at over eight NAPS stations from 2016 to 2018 ranged from 1.3 × 10-6 mg/m3 to 1.7 × 10-6 mg/m3 (NAPS 2016, 2017, 2018). Matched indoor, outdoor, and personal air monitoring data (PM2.5 samples) were collected from Windsor, Ontario, in 2005 and 2006 (Rasmussen et al. 2018). The highest median titanium concentration in this study was measured in outdoor air (1.9 × 10-6 mg/m3), followed by indoor air (1.4 × 10-6 mg/m3) and personal air (0.64 × 10-6 mg/m3) (Rasmussen et al. 2018).
Titanium was measured in various studies of Canadian outdoor air quality conducted by Health Canada between 2009 and 2013. Median PM2.5 titanium concentrations in outdoor air ranged from 4.2 × 10-7 mg/m3 in the winter of 2010 in Annapolis Valley, Nova Scotia, to 3.5 × 10-6 mg/m3 in the summer of 2010 in Sault Ste. Marie, Ontario (personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced ). Furthermore, titanium concentrations in various studies of Canadian indoor air quality conducted by Health Canada between 2009 and 2013 found median PM2.5 titanium concentrations in indoor air ranging from 2.6 × 10-7 mg/m3 in the summer of 2009 in Halifax, Nova Scotia, to 5.5 × 10-6 mg/m3 in the fall of 2013 in Ottawa, Ontario (personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced).
Titanium is present and detected in Canadian urban house dust (n=818), at a median concentration of 2,100 µg/g (Rasmussen et al. 2022). The median indoor (1.4 × 10-6 mg/m3) and outdoor (1.9 × 10-6 mg/m3) air concentrations measured in Windsor, Ontario, and the median concentration of titanium in Canadian house dust (2,100 µg/g) were used to estimate daily intake from environmental media.
Areas near point sources of titanium release (for example, a mine, smelter, or certain industrial manufacturing or processing facility) may have elevated levels of titanium in environmental media (Jin and Berlin 2015; Woodruff et al. 2017). Because releases of titanium are not reportable to the NPRI, a complete list of sectors releasing titanium in Canada could not be identified; however, certain sectors using titanium have been identified in the literature. In 2017, Rio Tinto Fer et Titane reported air emissions of 354 tonnes of total PM per year from their titanium ore mining facility located near Havre-Saint-Pierre, Québec, and 1,254 tonnes of total PM from their associated metallurgical complex located near Sorel-Tracy, Québec (NPRI [modified 2022]). Titanium is a component of total PM released from industrial facilities, but in the absence of data on the speciation of PM from the titanium industry in Canada, releases of titanium to air from the titanium industry in Québec could not be quantified. Iron and steel mills and the ferroalloy manufacturing industry (NAICS code 331110) are potential point sources of titanium release to air due to the use of titanium in the production of steel alloys.
Maximum point of impingement titanium dioxide concentrations were modelled by ArcelorMittal Dofasco, a large Canadian steel mill located in Hamilton, Ontario, as a requirement of Ontario Regulation (O.Reg. 419/05) (ArcelorMittal Dofasco 2018, 2019, 2020). Between the operating years of 2017 and 2019, the modelled maximum point of impingement titanium dioxide concentrations ranged from 3.8 × 10-4 mg Ti/m³ to 6.6 × 10-4 mg TiO2/m³, equivalent to 2.3 × 10-4 mg Ti/m³ to 4.0 × 10-4 mg Ti/m³, respectively.
Additionally, Heath Canada conducted air monitoring studies in areas near industrial facilities, including near a steel mill in Sault Ste. Marie, Ontario (n=105), near a shale gas plant in Penobsquis, New Brunswick (n=55), and near a port in Halifax, Nova Scotia (n=512) (personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced). The median titanium PM2.5 air concentrations in these studies ranged from 7.3 × 10-7 mg Ti/m³ to 3.5 × 10-6 mg Ti/m³ (personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced). Furthermore, median concentrations of titanium in PM2.5 samples from monitoring sites in the vicinity of oil sands in Northeastern Alberta were between 7.8 × 10-7 mg/m3 and 2.0 × 10-6 mg/m3 (n=230) in 2018 and between 8.1 × 10-7 mg/m3 and 2.2 × 10-6 mg/m3 (n=302) in 2019 (WBEA 2019, 2020).
Airborne titanium concentrations up to 1 × 10-3 mg/m3 have been reported from air monitoring in industrialized areas in the US (IPCS 1982; Jin and Berlin 2015; Woodruff et al. 2017). The air concentration reported in industrialized areas in the US was used as surrogate data to estimate inhalation exposure to ambient air with point source influence. Uncertainty remains as to whether titanium air concentrations in proximity to titanium ore mining and refining facilities are higher than the air concentrations in industrial areas in the US.
In studies conducted by Health Canada, titanium was measured in PM2.5 samples of indoor, outdoor, and personal air with influence from public transit, personal vehicles, and indoor and outdoor air from schools. Titanium was measured in samples of PM2.5 from subways, buses, and private cars in large Canadian cities as part of Health Canada’s urban transport exposure study conducted in Montreal, Ottawa, Toronto, and Vancouver (personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced). In a total of 18 samples, median annual titanium air concentrations in personal air samples on subways (4.2 × 10-6 mg/m3 to 1.9 × 10-5 mg/m3) and buses (6.0 × 10-6 mg/m3 to 8.0 × 10-6 mg/m3) were higher than average indoor and outdoor titanium air concentrations. Although these values suggest that public transit may be a point source of human exposure to titanium, the data are insufficient to draw a conclusion. Median annual titanium air concentrations outside of private cars (7.3 × 10-6 mg/m3 to 1.6 × 10-5 mg/m3) were higher than those inside private cars (6.1 × 10-6 to 1.0 × 10-5 mg/m3) but lower than the highest median annual personal air concentration reported on subways (personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced). Daily intake of titanium from air on public transit was not factored into the daily intake estimates in this exposure assessment but was considered a point source of inhalation exposure in the risk characterization (Table 5-1).
Titanium was also measured in PM2.5 samples from indoor and outdoor air in four schools in fall 2013 in Ottawa, Ontario. The median titanium concentration in indoor air was 5.5 × 10-6 mg/m3 (n=133), and the median titanium concentration in outdoor air was 2.2 × 10-6 mg/m3 (n=125) (personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced). Titanium concentrations measured in air in schools were greater than average titanium concentrations measured in ambient air. However, since sampling was limited to four schools, the difference between school and ambient air concentrations may not be statistically significant, and the measured air concentration may not be representative of schools across Canada. Similar to public transit, daily intake of titanium from air in schools was not factored into the daily intake estimates in this exposure assessment but was considered a point source of inhalation exposure in the risk characterization (Table 5-4 ).
To compare exposure between age groups, estimates of daily titanium intake from environmental media, food, and drinking water were derived and presented in Appendix A, Table A‑5. Intake of titanium from environmental media, food, and drinking water ranged from 8.1 × 10-3 mg/kg bw/day for formula-fed infants 0 to 5 months old to 4.1 mg/kg bw/day for children 4 to 8 and 9 to 13 years old. Diet was the primary source of exposure for human milk-fed infants 0 to 5 months old and all age groups aged 6 months and older. For formula-fed infants 0 to 5 months old, dust was the primary source of exposure, followed by diet. The estimated dietary intake of titanium from country foods in Northern Saskatchewan will not be brought forward for risk characterization, as the highest estimated intake of 2.4 × 10-3 mg Ti/kg bw/day for 1-year-old children in Stony Rapids is lower than the highest mean daily intake of 4.1 mg/kg bw/day for children between 4 and 13 years old in the general Canadian population.
| Exposure scenario | Ti daily air concentrations (mg/m3) |
|---|---|
| Environmental media, PM2.5 daily air concentrationa | 1.5 × 10-6 |
| Environmental media, daily air concentration point source influenceb | 1.0 × 10-3 |
| Environmental media, PM2.5 daily air concentration, transit influencec | 2.7 × 10-6 |
| Environmental media, PM2.5 daily air concentration, school influenced | 2.6 × 10-6 |
Abbreviations: mg/m3, milligram per cubic metre
a Daily air concentration estimated using median 24-hour outdoor air sample PM2.5 of 1.9 × 10-6 mg/m3 (n=121) measured in Windsor, Ontario (Rasmussen et al. 2018), and median annual 24-hour indoor air sample PM2.5 of 1.4 × 10-6 mg/m3 (n=121) measured in Windsor, Ontario (Rasmussen et al. 2018). People living in Canada are assumed to spend 3 hours outdoors and 21 hours indoors each day (Health Canada 1998). Daily air concentration = (concentration Ti outdoor air × [3 hours/24 hours]) + (concentration Ti indoor air × [21 hours/24 hours]).
b Daily air concentration, point source influence estimated using the ambient air concentration reported in industrialized areas in the US of 1.0 × 10-3 mg/m3 (IPCS 1982; Jin and Berlin 2015; Woodruff et al. 2017). In the absence of data on titanium concentration in indoor air in the vicinity of a point source of release, the titanium air concentration is assumed to be constant over a 24-hour period each day.
c Daily air concentration, transit influence estimated using median 24-hour PM2.5 personal air sample from subway of 1.8 × 10-5 mg/m3, and median 24-hour outdoor air sample PM2.5 of 1.9 × 10-6 mg/m3 (n=121) measured in Windsor, Ontario (Rasmussen et al. 2018). The largest median PM2.5 titanium concentration reported in data sets from Ottawa, Toronto, Montreal, and Vancouver was assumed to represent median titanium air concentration as a conservative assumption. For time not spent on transit, the titanium concentration in outdoor air is used as a conservative assumption, as it is higher than the titanium concentration in indoor air. Individuals are assumed to spend 70 minutes on transit per day (van Ryswyk et al. 2017). Daily air concentration, transit influence = (concentration Ti personal air, subway × [70 minutes/1440 minutes]) + (concentration Ti outdoor air × [1370 minutes/1440 minutes]).
d Daily air concentration, school influence estimated using median 24-hour outdoor air sample PM2.5 of 1.9 × 10-6 mg/m3 (n=121) measured in Windsor, Ontario (Rasmussen et al. 2018), median 24-hour indoor air sample PM2.5 of 1.4 × 10-6 mg/m3 (n=121) measured in Windsor, Ontario (Rasmussen et al. 2018), and median 8-hour personal indoor air sample PM2.5 of 5.5 × 10-6 mg/m3 (n=133) measured in the 2013 Ottawa School Study (personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced). School-aged people living in Canada are assumed to spend 3 hours outdoors and 14.5 hours indoors each day and 6.5 hours indoors at school (Health Canada 1998; MacNeill et al. 2016). Daily air concentration, school influence = (concentration Ti outdoor air × [3 hours/24 hours]) + (concentration Ti indoor air × [14.5 hours/24 hours]) + (concentration Ti indoor school air × [6.5 hours/24 hours]).
5.2.2 Products available to consumers
The 13 titanium-containing substances have widespread industrial, commercial, and consumer uses that may contribute to daily exposure. As outlined in the sources and uses section, substances in the Titanium-containing Substances Group are present in a range of products available to consumers. Exposures to titanium from products available to consumers that are used daily or frequently, where use may contribute to systemic levels of titanium, are captured in the biomonitoring data. Inhalation exposure may result in portal-of-entry effects in the lungs. Therefore, exposure was estimated for products available to consumers that could lead to potential inhalation exposure to titanium (Table 5‑2).
Inhalation exposure assessment of the Titanium-containing Substances Group
In Canada, titanium tetraisopropanolate, titanium tetrakis(2-ethylhexanolate), rutile (TiO2), dititanium trioxide (Ti2O3), and titanium dioxide (TiO2) (CAS RNs 549-69-9, 1070-10-6, 1317-80-2, 1344-54-3, and 13463-67-7, respectively) were found in a range of aerosol or spray products and loose powder products whose use may result in inhalation exposure. These products include self-care products (that is, cosmetics, natural health products, and non-prescription drugs), arts and crafts materials and toys (for example, chalk, powder paint), disinfectant surface spray, powdered dish detergent, aerosol water repellant spray, aerosol boot protector spray, aerosol adhesives and sealants, spray automotive products, paints and coatings, cement, spray ceiling and wall texture, tile grout, and floor coatings (personal communication, emails from the CHPSD, Health Canada, to the ESRAB, Health Canada, dated between March 29, 2018, and December 8, 2020; unreferenced; personal communication, email from the NNHPD, Health Canada, to the ESRAB, Health Canada, dated March 9, 2018; unreferenced; personal communication, email from the PDD, Health Canada, to the ESRAB, Health Canada, dated March 6, 2018; unreferenced; Health Canada 2019; CPID [modified 2022]; CPISI [modified 2022]; SCHEER 2023). The other eight substances in the Titanium-containing Substances Group were not found in products available to consumers that may result in inhalation exposure. All concentrations of titanium-containing substances in products available to consumers were converted to titanium equivalents on the basis of composition and molecular weight. Exposure estimates for products resulting in the highest air concentrations of titanium from each product category are included in this exposure assessment.
Air concentrations of titanium from the use of aerosol and trigger or pump spray products were modelled using the Consumer Exposure Web Model v.1.0.7 (ConsExpo Web 2020), a computational modelling program intended to estimate exposure of the general population to products available to consumers. Refinements to certain default model parameters for aerosol and spray product scenarios were made in order to generate the most relevant exposure estimates for each type of sentinel self-care product. Air concentrations were estimated for the use of self-care products formulated as aerosols and trigger or pump sprays, including aerosol sunscreen spray, aerosol body makeup, aerosol hair styling spray, and aerosol temporary hair colour. Concentrations of titanium in aerosol and trigger or pump spray self-care products ranged from 0.06% to 18% (personal communication, emails from the CHPSD, Health Canada, to the ESRAB, Health Canada, dated between March 29, 2018, and December 8, 2020; unreferenced; personal communication, email from the TPD, Health Canada, to the ESRAB, Health Canada, dated March 6, 2018; unreferenced). Air concentrations of titanium from the use of aerosol and trigger or pump spray products were amortized over 24 hours to generate mean daily air concentrations. The highest estimated amortized daily air concentration from aerosol and trigger or pump spray self-care products was 2.8 × 10-3 mg Ti/m3 from the use of aerosol leg foundation spray. This scenario is presented as the sentinel exposure scenario and covers exposure from other aerosol and trigger or pump spray self-care products. The ConsExpo Web spray model (non-volatile exposure to spray) used to estimate the inhalable air concentration of spray particles includes an input for a maximum diameter, but there is no input for the minimum or lower-bound size.
In addition to self-care product uses, scenarios were modelled to estimate exposure from the use of a spray disinfectant product, and the use of an aerosol spray paint can (personal communication, email from the TPD, Health Canada, to the ESRAB, Health Canada, dated March 6, 2018; unreferenced; Health Canada 2019; CPID [modified 2022]). Mean daily air concentrations were derived by amortizing exposure over 24 hours and considering the frequency of use of spray disinfectant product and aerosol spray paint can. Estimated mean daily air concentration from the use of a spray disinfectant was 2.5 × 10-3 mg Ti/m3, while the mean daily air concentration from the use of an aerosol spray paint can was 4.5 × 10-3 mg Ti/m3.
Air concentrations were also estimated for self-care products formulated as loose powders with the potential for inhalation of respirable titanium-containing particles. These products include body powder, powdered face makeup, and powdered face makeup with SPF. Concentrations of titanium in powdered self-care products ranged from 0.06% to 60% (personal communication, emails from the CHPSD, Health Canada, to the ESRAB, Health Canada, dated between March 29, 2018, and December 8, 2020; unreferenced; personal communication, email from the NNHPD, Health Canada, to the ESRAB, Health Canada, dated March 9, 2018; unreferenced). Products formulated as pressed powders were not identified as a potential exposure source of concern because these formulations contain coarser particles and binders, such as oils or waxes, that bind the particles together and do not result in the formation of a “dust cloud” that may be inhaled during product use.
Air concentrations of powdered self-care products were estimated using experimentally measured average PM air concentration data of poorly soluble particles from the use of loose powdered cosmetics. Several studies of air concentrations generated from the use of powdered self-care products were considered (Nazarenko et al. 2012; Anderson et al. 2017; Rasmussen et al. 2019; Oh et al. 2021). Nazarenko et al. (2012) measured the air concentration of PM from the simulated use of cosmetic powders in particle number concentrations. Oh et al. (2021) measured air concentrations generated from the simulated use of eyebrow powders in mass concentration. Data from Nazarenko et al. (2012) were not used to estimate air concentrations of titanium dioxide from the use of powdered self-care products in this exposure assessment, as the mass per volume air concentration data were not reported (only number of particles per volume of air were provided). Data from Oh et al. (2021) were not used to estimate air concentrations of titanium dioxide from the use of powdered self-care products in this exposure assessment, as the product type (eyebrow powder) could result in the underestimation of air concentrations from body powders and face powders, which may be used in larger amounts and applied over a greater body surface area.
Of the available data, Anderson et al. (2017) and Rasmussen et al. (2019) provide the best and most relevant data for modelling the product scenarios included in this exposure assessment, as the data in these studies are reported in mass concentration and the products analyzed are representative of the product types considered in this exposure assessment. In studies by Anderson et al. (2017) and Rasmussen et al. (2019), average PM4 (particulate matter with an aerodynamic diameter of 4 μm or less) concentrations of talc, a poorly soluble mineral common in cosmetics, were estimated from the use of loose body and face powder products. Average air concentrations from Anderson et al. (2017) were combined with the body and face replicates from Rasmussen et al. (2019), resulting in an overall average PM4 event air concentration of 1.36 ± 0.97 mg/m3 (ECCC, HC 2021). This average air concentration value includes particles ranging in size from <1 µm to 8 µm and may include some nano-sized particles. However, the contribution to the mass concentration estimates would likely be negligible due to the small proportion of nano-sized particles measured by Rasmussen et al. (2019). This air concentration was used to estimate air concentrations of titanium from the use of self-care products based on the the concentration of titanium in the products. The use of talc PM4 data as a surrogate for titanium is based on their physical similarities as poorly soluble particles and their use in similar types of products available to consumers. The highest estimated mean daily air concentration from loose powder self-care products was 2.8 × 10-3 mg Ti/m3 from the use of loose powder face makeup. This scenario is presented as the sentinel exposure scenario and covers exposure from other loose powder self-care products.
Air concentrations of titanium dioxide from the use of chalk were estimated using experimentally measured average PM air concentration data from studies on the use of chalk. Several studies of air concentrations generated from the use of chalk were considered (Majumdar et al. 2012; Lin et al. 2015; Goel et al. 2017; Sekar et al. 2021). The average PM10 concentration of 0.39 mg/m3 was calculated from data reported by Majumdar et al. (2012), Lin et al. (2015), Goel et al. (2017), and Sekar et al. (2021). This value was then adjusted using the concentration of titanium dioxide in chalk reported by SCHEER (2023), resulting in an estimated average daily air concentration of 6.3 × 10-3 mg/m3 from the use of chalk.
Additionally, scenarios were modelled to represent the pouring of solid powder prior to mixing, reflecting potential inhalation exposure from mixing a powdered bath product into a bath, pouring powdered dish detergent, and mixing tile grout. Air concentrations of titanium generated from pouring powdered products were estimated using arithmetic mean unit exposure data from the human exposure solid pour (powder and granule) study submitted by the Exposure Assessment Task Force II (AEATF II) to the US EPA (2016). Eight-hour time-weighted average (TWA) air concentration estimates were generated using the AEATF II 8-hour TWA unit exposure for open pour powder exposure from open pouring to antimicrobial products (5.5 × 10-3 mg/m3/lb ai) (US EPA 2016). Although the AEATF II 8-hour TWA unit exposure is representative of inhalable (total) particulates, the particle size range was not reported in publicly available sources. Mean daily air concentrations were derived by amortizing exposure over 24 hours based on the duration of exposure and frequency of use. Mean daily air concentrations from pouring powdered products available to consumers ranged from 1.1 × 10-6 mg Ti/m3 to 1.3 × 10-5 mg Ti/m3.
The exposure scenarios for aerosol, spray, and loose powdered products that resulted in the highest air concentrations are presented in Table 5‑2. Adjusted 4-hour air concentrations were derived for products with infrequent or intermittent use patterns. On the basis of the duration and nature of effects observed in the toxicity data used to characterize risk, the mean event air concentrations of titanium from the use of products were amortized over 24 hours based on duration of exposure and frequency of use to represent continuous exposure. Details of all exposure scenarios and input values for the models are provided in Appendix B, Table B‑1, including refinements to defaults.
| Product category | Exposure scenario | Age groupa | Mean event air concentration (mg Ti/m3) | Adjusted 4-hour air concentration (mg Ti/m3)b | Mean daily air concentration (mg Ti/m3) |
|---|---|---|---|---|---|
| Self-care, cosmetic | Using leg foundation (spray) | Adult | 0.8 | N/A | 2.8 × 10-3 |
| Self-care, cosmetic | Using face makeup (loose powder) | Adult | 0.82 | N/A | 2.8 × 10-3 |
| Self-care, cosmetic | Pouring powdered bath product | Adult | 1.4 × 10-4 c | N/A | 1.3 × 10-5 |
| Self-care, cosmetic | Using temporary hair colour (spray) | Adult | 0.9 | 1.9 × 10-2 | 5.9 × 10-5 |
| Cleaning product, (NPD–NMI) | Using surface disinfectant spray | Adult | 3.6 × 10-2 | N/A | 1.5 × 10-3 |
| Cleaning product | Pouring powdered dish detergent | Adult | 3.3 × 10-6 c | N/A | 1.1 × 10-6 |
| Paints and coatings | Aerosol spray can | Adult | 59 | 4.9 | 4.5 × 10-3 |
| DIY product | Pouring powdered tile grout | Adult | 1.8 × 10-2 c | 3.6 × 10-2 | 8.4 × 10-6 |
| Arts and crafts materials and toys | Using chalk | Child | 2.0 × 10-2 | 3.8 × 10-3 | 6.3 × 10-4 |
Abbreviations: N/A, not applicable; NMI, non-medicinal ingredient; NPD, non-prescription drug; mg/m3, milligram per cubic metre
a Age group(s) identified are those with the highest estimated daily exposure based on the event air concentration and frequency of use.
b Air concentrations are adjusted to 4-hour average air concentrations to match the duration of exposure in the acute hazard study. Adjusted 4-hour air concentration (mg/m3) = Mean event air concentration (mg/m3) × (Exposure duration [hour] / 4 hours).
c The reported mean event air concentration is an 8-hour TWA air concentration based on the availability of unit exposure values.
Additional use scenarios with the potential for inhalation exposure to titanium dioxide were considered, including aerosol fragrance, pump body spray, aerosol body moisturizer, aerosol sunscreen, aerosol sunless tanning products, aerosol hair spray, aerosol dry shampoo, aerosol face makeup, aerosol face moisturizer, aerosol nail polish, powdered deodorant, powdered body moisturizer, powdered body makeup, other loose powdered makeup products (for example, blush, eyeshadow), powdered face cleanser, pneumatic paint sprayer, aerosol adhesives and sealants, spray ceiling and wall texture, and spray floor coatings. However, they resulted in lower mean daily air concentrations than those presented in Table 5‑2. Adjusted 4-hour exposures from products with infrequent or intermittent use patterns were calculated but were not brought forward for risk characterization, as no effects were observed in acute toxicity studies. Estimated exposures from products with infrequent or intermittent use patterns were adjusted to continuous exposure scenarios and considered as the sentinel exposure scenarios in the risk characterization, where applicable.
5.2.3 Biomonitoring data
Total titanium concentration in whole blood was used to estimate exposure of the general population to the Titanium-containing Substances Group. The human health risks of oral exposure to the 13 titanium-containing substances were characterized using the Biomonitoring-based Approach 2 (Health Canada 2016a). The Biomonitoring-based Approach 2 compares human biomonitoring data (as a measure of exposure) against biomonitoring guidance values that are consistent with available health-based exposure guidance values, such as BEs, to assess whether substances are of low concern for human health. Total concentrations of titanium in whole blood provide a biologically relevant, integrated measure of systemic exposure that may occur across multiple routes (for example, oral, dermal, and inhalation) and from various sources, including environmental media, food, and frequent- or daily-use of products available to consumers.
Given that ubstance-specific exposure data are very limited, data on the total metal moiety was considered to be an acceptable, conservative surrogate, as total metal moiety biomonitoring data include exposures from all bioavailable forms of the element. Therefore, exposure characterization of systemic effects through this moiety-based approach may be applicable to titanium-containing substances beyond the substances included in the Titanium-containing Substances Group.
The Titanium-containing Substances Group did not meet the criteria to be assessed using Biomonitoring-based Approach 1 (Health Canada 2016b), as the limit of detection in available biomonitoring data was not sufficiently low (Jayawardene et al. 2021). Sufficient high-quality biomonitoring data exist for titanium to adequately characterize exposure to the Canadian population, including specific subpopulations of interest who may have the potential for elevated exposure, such as children, pregnant women and pregnant people, and certain Indigenous populations.
Whole blood titanium concentrations for the Canadian population were generated in a biobank project (Jayawardene et al. 2021). In this project, whole blood samples, collected and preserved from the Canadian Health Measures Survey (CHMS) Cycle 2 (5,752 samples), were analyzed by inductively coupled plasma-mass spectrometry at Health Canada’s Health Products Laboratory in Longueuil, Québec, for their titanium concentrations (Health Canada 2013; Jayawardene et al. 2021). The CHMS is a national survey carried out by Statistics Canada in partnership with Health Canada and the Public Health Agency of Canada, which collects information from people living in Canada about their general health (Health Canada 2013). It is designed to be nationally representativeFootnote 8 and includes a biomonitoring component. Since the CHMS is not a targeted survey, it does not target individuals with known high levels of metal exposure nor those living near point sources of exposure. The CHMS Cycle 2 samples were collected between 2009 and 2011 from people living in Canada aged 3 to 79, including pregnant women and both fasting and non-fasting individuals, at 18 sites across Canada (Health Canada 2013). Titanium was not detected in 99.97% of the Canadian population (aged 3 to 79), at or above the limit of detection of 10 µg/L (Table 5‑3) (Jayawardene et al. 2021). The median and 95th percentile titanium concentrations were below the limit of detection.
| Substance | Number of samples | LOD (µg/L) | Median (µg/L) | 95th percentile (µg/L) | Detection frequencya |
|---|---|---|---|---|---|
| Titanium | 5,752 | 10 | <10 | <10 | 0.03 |
Abbreviations: LOD, limit of detection; µg/L, microgram per litre
a Percent of the population with concentrations at or above the limit of detection (10 µg/L).
In addition to population-level CHMS biomonitoring data, Canadian data from pregnant women in Northern Saskatchewan and control or pre-operative data from studies that measured titanium concentrations in the blood of people with metallic orthopedic implants were considered. The studies were carefully selected for inclusion in this exposure assessment, as the analysis of titanium in complex matrices is susceptible to analytical challenges, such as spectral interferences in conventional analytical methods used for trace element determination and potential inadvertent contamination of samples (Rodushkin and Ödman 2001; Sampson and Hart 2012; Balcaen et al. 2014; Barry et al. 2020). A wide range of baseline whole blood and/or serum titanium concentrations has been reported in the literature in recent years. Some of the variations in baseline whole blood or serum titanium concentrations may be due to insufficient sensitivity and/or selectivity of conventional analytical methods used for trace element determination to accurately quantify trace levels of titanium in complex matrices such as whole blood and serum (Barry et al. 2020).
Titanium was included in the Northern Saskatchewan Prenatal Biomonitoring Study (Saskatchewan Ministry of Health 2019). In this study, a series of environmental chemicals and metals were monitored in the blood serum of pregnant women (n=841) residing in Northern Saskatchewan between 2011 and 2013 (Saskatchewan Ministry of Health 2019). The study was conducted in Northern Saskatchewan, which has a population of approximately 40,000 people across 70 communities. Close to 87% of the population residing in the area self-identify as Indigenous persons (Saskatchewan Ministry of Health 2019). Blood samples were pooled into six pools by geographical area. The median concentration of titanium measured in each of the geographic pooled samples was below the limit of detection of 5 μg/L.
Most of the available studies reporting titanium concentrations in blood focus on the use of titanium biomonitoring data to assess the condition and degradation of metallic orthopedic implants (Sampson and Hart 2012; Balcaen et al. 2014; Barry et al. 2020). Recent studies of patients with metallic orthopedic implants using highly sensitive and selective analytical methods have reported mean concentrations of titanium in whole blood and serum in pre-operative or control groups ranging from 0.2 μg/L to 2.5 μg/L (Dunstan et al. 2005; Richardson et al. 2008; Sarmiento-González et al. 2008; Engh et al. 2009; Vendittoli et al. 2010, 2011, 2013; Nuevo-Ordóñez et al. 2011; Barry et al. 2013, 2020; Omlor et al. 2013; Balcaen et al. 2014; Cundy et al. 2014; Gofton et al. 2015; Nam et al. 2015, 2019; Barlow et al. 2017; Koller et al. 2018; Temiz et al. 2018; Reiner et al. 2019). Furthermore, recent studies of titanium in blood using high resolution analytical methods consistently reported baseline levels of titanium lower than 1 μg/L (Swiatkowska et al. 2019).
Whole blood titanium concentrations from the CHMS will be used to characterize the systemic exposure of people living in Canada. This biomonitoring data is considered to be an integrated measure of systemic titanium from all routes and sources, including exposure from environmental media, food, drinking water, and frequent- or daily-use products. The CHMS biomonitoring data set includes people living in Canada aged 3 to 79 years and is considered to be protective of younger age groups not covered by the survey (under 3 years of age), as children aged 4 to 13 had the highest intake from environmental media, food, and drinking water. Titanium blood concentrations indicate that population-level exposure is below the limit of detection of 10 μg/L. This is considered to be a conservative estimate when compared with titanium blood concentrations measured in pregnant women and Indigenous women in Northern Saskatchewan (<5 μg/L) and with data from control and pre-operative individuals in studies of metallic orthopedic implants (0.2 μg/L to 2.5 μg/L).
The Biomonitoring-based Approach 2 is not considered relevant for exposure assessment of portal-of-entry effects, such as lung effects from inhalation exposure, which was assessed separately in this assessment using standard exposure estimate methods.
5.2.4 Consideration of subpopulations who may have greater exposure
There are groups of individuals within the Canadian population who, due to greater exposure, may be more vulnerable to experiencing adverse health effects from exposure to substances. Certain subpopulations have the potential for increased exposure due to differences in physical characteristics (for example, body weight, breathing rate), life stage (for example, infancy, pregnancy), behaviours (for example, mouthing and ingestion of non-food items, crawling), cultural influences (for example, unique diets or product use), socio-economic factors (for example, substandard housing, limited consumer choice), or geographical differences (for example, living in the vicinity of commercial or industrial facilities). The potential for elevated exposure to titanium within the Canadian population was examined. Exposure estimates are routinely assessed by age to account for physical and behavioural differences during different life stages. Where data are available, additional exposure factors are taken into consideration.
In this exposure assessment, exposure estimates from environmental media, food, drinking water, human milk, infant formula, and products available to consumers were derived for different age groups to account for differences in physiology, life stage, and behaviours. Children aged 4 to 13 had higher intakes from environmental media, food, and drinking water than adults. Intake of titanium from the consumption of country foods by Indigenous populations in Northern Saskatchewan was lower than the estimated mean dietary intake of titanium for the general population. Biomonitoring data were available for the Canadian population from the CHMS, as well as from pregnant women and Indigenous women living in Northern Saskatchewan. An analysis of the potential for elevated exposure within the Canadian population could not be conducted, as concentrations of titanium in the CHMS biomonitoring data were consistently below the limit of detection. However, the CHMS biomonitoring data brought forward to risk characterization were protective of exposures measured in pregnant women and Indigenous women from Northern Saskatchewan because the detection limit reported for CHMS data is higher than that of other biomonitoring studies. In addition, measured and modelled environmental media data were available to characterize airborne titanium exposure among children in school, transit users, and people living in the vicinity of industrial point sources. Airborne titanium concentrations were higher near industrial point sources compared with ambient air concentrations. All of these factors were considered when characterizing exposure and risk to people living in Canada.
5.3 Risk characterization
The potential for cumulative effects was considered in this assessment by examining cumulative exposures from the broader moiety of titanium. Due to the availability of adequate and representative Canadian biomonitoring data and a biomonitoring guidance value for titanium (that is, a BE), characterization of the potential for harm to human health resulting from systemic exposure to the Titanium-containing Substances Group was based on the Biomonitoring-based Approach 2, as noted in section 5.2.3 (Health Canada 2016a).
Systemic exposure oif the Canadian population to total titanium was characterized using biomonitoring data from the CHMS (Cycle 2). These data are representative of exposures that may occur across multiple routes and from various sources, including environmental media, food, and frequent- or daily-use products available to consumers. The 95th percentile whole blood titanium concentration was below the detection limit of 10 µg/L (Table 5‑3) and was not detected in 99.97% of the Canadian population (Jayawardene et al. 2021). Available biomonitoring data, estimated intakes from environmental media and diet, and estimated intake from country foods indicate that the CHMS data are considered to be protective of titanium measured in Indigenous populations and pregnant women in Canada, as well as in infants and children. Although no biomonitoring data from the CHMS Cycle 2 biobank are available for children under 3 years of age, exposure in this age group from environmental media, food, and drinking water is lower than in children aged 4 to 13, who are captured in the CHMS data set.
A multi-compartmental pharmacokinetic model published by Ramoju et al. (2020) was used to derive a whole blood BE of 65 µg/L for the NOAEL of 623 mg Ti/kg bw/day , with an UF of 25 (2.5x interspecies toxicodynamics and 10x for intraspecies variation). Exposure to total titanium in the Canadian population, characterized by the detection limit of titanium in whole blood of 10 µg/L, was below the derived BE of 65 µg/L and considered low enough to account for uncertainties in the health effects and exposure data used to characterize risk. This indicates that, at current levels of systemic exposure, the 13 titanium-containing substances are of low concern to the health of the general population of Canada.
For inhalation exposure, inhalation toxicity data for titanium dioxide were used as surrogate data for risk characterization of inhalation exposure of the 13 titanium-containing substances in the group.
The LOAEC of 10 mg TiO2/m3 (6.0 Ti/m3), based on treatment-related lung effects (portal-of-entry effects) in rats from Lee et al. (1985), was selected as the critical POD for risk characterization of chronic inhalation exposure to titanium in the general population. The LOAEC (that is, 10 mg TiO2/m3) was converted to a continuous titanium exposure concentration of 1.1 mg Ti/m3 as detailed in section 5.1.4. The titanium dioxide-derived critical POD was converted to an equivalent titanium concentration to support its use for all titanium-containing substances in the group. This value was adjusted for continuous exposure to account for differences in exposure duration between the animals tested in the critical health effects study and the duration of exposure from the use of products available to consumers. Episodic exposures from product use are expected to increase lung load over time due to slow lung clearance of titanium particles. The risk from acute inhalation exposures to titanium was not quantified, as no adverse effects were observed up to the limit dose of 5,090 mg TiO2/m3 (3,051 mg Ti/m3) tested in an acute inhalation study (REACH [modified 2022]).
Measurements of titanium in PM in air, including indoor, outdoor, and ambient air in proximity to point sources of exposure, were used to characterize inhalation exposure to titanium-containing substances. A comparison of the LOAEC of 1.1 mg Ti/m3 for portal-of-entry effects to air concentrations of titanium in outdoor, personal, and ambient air in proximity to point sources resulted in route-specific margins of exposure (MOEs) ranging from 1,100 to 733,333 (Table 5-4). In addition, there is potential for inhalation exposure to titanium-containing substances from the use of spray products (aerosol, pump) and loose powder products available to consumers. Exposure estimates were derived for sentinel exposure scenarios to characterize risk to the general population. A comparison of the LOAEC of 1.1 mg Ti/m3 for portal-of-entry effects and the estimated air concentrations of titanium from the use of spray and loose powder products available to consumers resulted in MOEs ranging from 245 to 995,133 (Table 5‑5).
The MOEs derived for inhalation exposure are considered adequate to protect the general population from route-specific adverse effects of inhalation exposure to titanium from products available to consumers. Given the conservative parameters used to model exposures and the critical endpoint from a chronic inhalation study, the calculated MOEs are considered adequate to account for uncertainties in the inhalation health effects and exposure data used to characterize risk.
| Exposure scenario | Daily Ti air concentrations (mg/m3) | MOEa,b |
|---|---|---|
| Environmental media, PM2.5 daily air concentration | 1.5 × 10-6 | 733,333 |
| Environmental media, daily air concentration point source influence | 1.0 × 10-3 | 1,100 |
| Environmental media, PM2.5 daily air concentration, transit influence | 2.7 × 10-6 | 407,407 |
| Environmental media, PM2.5 daily air concentration, school influence | 2.6 × 10-6 | 423,077 |
Abbreviations: mg/m3, milligram per cubic metre; MOE, margin of exposure
a MOEs were calculated using the POD of 1.1 mg Ti/m3 for portal-of-entry effects from the LOAEC of 6 Ti/m3, from Lee et al. (1985), adjusted for continuous exposure.
b Target MOE = 300 (10x interspecies variation; 10x intraspecies variation; 3x for LOAEC extrapolated to NOAEC).
| Product category and exposure scenario | Mean daily air concentrations (mg Ti/m3)a | MOEb, c |
|---|---|---|
| Self-care, cosmetic; Applying leg foundation; Adult | 2.8 × 10-3 | 393 |
| Self-care, cosmetic; Using face makeup (loose powder); Adult | 2.8 × 10-3 | 393 |
| Self-care, cosmetic; Pouring powdered bath product; Adult | 1.3 × 10-5 | 84,556 |
| Cleaning product, NPD – NMI; Using disinfectant (spray); Adult | 1.5 × 10-3 | 733 |
| Cleaning products; Pouring powdered dish detergent; Adult | 1.1 × 10-6 | 995,133 |
| Paints and coatings; Aerosol spray paint can; Adult | 4.5 × 10-3 | 245d |
| Arts and crafts materials and toys; Using chalk; Child | 6.3 × 10-4 | 1,789 |
Abbreviations: mg/m3, milligram per cubic metre; MOE, margin of exposure; NMI, non-medicinal ingredient; NPD, non-prescription drug
a Estimated air concentrations for titanium exposure were amortized over 24 hours, based on duration of exposure and frequency of use, to represent the average daily air concentration.
b MOEs were calculated based on the POD of 1.1 mg Ti/m3 for portal-of-entry effects from the LOAEC of 6 Ti/m3 from Lee et al. (1985), adjusted for continuous exposure.
c Target MOE = 300 (10x interspecies variation; 10x intraspecies variation; 3x for LOAEC to NOAEC).
d Considered adequate due to conservativisms in the ConsExpo model parameters used to generate the exposure estimate and the reversibility of effects that would be expected between intermittent exposures.
5.4 Uncertainties in the evaluation of risk to human health
There is some uncertainty concerning the use of toxicokinetic and toxicity data from titanium dioxide as surrogate data for all titanium-containing substances in the group.
Uncertainties associated with Biomonitoring-based Approach 2 (Health Canada 2016a) may include limited pharmacokinetic data used in the derivation of a biomonitoring guidance value, as well as variability in the quality and robustness of data available for the derivation of a biomonitoring guidance value (for example, BE) for titanium. In addition, it is difficult to identify sources of exposure using biomonitoring data alone; therefore, this human health assessment also considers information on sources and uses.
The pharmacokinetic model used for BE derivation assumed that the kinetic properties of i.v. exposure are applicable to simulating oral exposure scenarios. Although some uncertainty is associated with this assumption, this approach is consistent with the evidence provided by various animal and human oral studies of titanium dioxide microparticles.
The relevance of the exposure biomarker to dose metrics for titanium is considered low to medium. Uncertainty remains due to low and variable oral bioavailability confounded by background levels (EFSA 2016) and the lack of any significant data correlating the degree of toxicity with blood titanium concentration.
Although health effects of nanoscale particles have been reported for both oral and inhalation exposures, the toxicity associated with nanoscale particles is not explicitly considered in this human health assessment. Some titanium-containing substances, such as food-grade titanium dioxide, contain both nanoscale and microscale particles. However, the particle size distribution of food-grade titanium dioxide (including the percentage of nanoparticles that may be present) may vary, resulting in uncertainty regarding the particle size range in food-grade titanium dioxide that people living in Canada are exposed to, as well as the extent to which titanium dioxide test materials used in research studies resemble the forms and degree of dispersion or agglomeration/aggregation state of food-grade titanium dioxide potentially found in food in Canada.
Additionally, it is unclear whether other substances in the Titanium-containing Substances Group also contain nanoscale fractions. The range of particle sizes included in the data and models used to quantify exposure from products available to consumers is variable or unknown. While some exposure estimates may include contributions from nanoscale particles, these are expected to represent a minor contribution to the overall mass-based air concentration available for inhalation. The Government of Canada has committed to further addressing nanoscale forms of substances on the DSL, including nanoscale titanium dioxide (ECCC, HC 2022; Health Canada [modified 2022a]).
6. Conclusion
Considering all available evidence presented in this assessment, there is low risk of harm to the environment from the 13 substances in the Titanium-containing Substances Group. It is concluded that the 13 substances in the Titanium-containing Substances Group do not meet the criteria set out in paragraphs 64(a) or (b) of CEPA as they are not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends.
Considering all available lines of evidence presented in this assessment, it is concluded that the 13 substances in the Titanium-containing Substances Group do not meet the criteria set out in paragraph 64(c) of CEPA as they are not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health. It is therefore concluded that the 13 substances in the Titanium-containing Substances Group do not meet any of the criteria set out in section 64 of CEPA.
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Yan J, Wang D, Li K, Chen Q, Lai W, Tian L, Lin B, Tan Y, Liu X, Xi Z. 2020. Toxic effects of the food additives titanium dioxide and silica on the murine intestinal tract: mechanisms related to intestinal barrier dysfunction involved by gut microbiota. Environ Toxicol Pharmacol. 80:103485.
Zijno A, De Angelis I, De Berardis B, Andreoli C, Russo MT, Pietraforte D, Scorza G, Degan P, Ponti J, Rossi F, et al. 2015. Different mechanisms are involved in oxidative DNA damage and genotoxicity induction by ZnO and TiO2 nanoparticles in human colon carcinoma cells. Toxicol In Vitro. 29(7):1503–1512.
Appendix A. Exposure to environmental media, food, and drinking water
| Age groups | Body weight (kg) | Inhalation rate (m3/day) | Soil ingestion rate (µg/day) | Dust ingestion rate (µg/day) |
|---|---|---|---|---|
| 0 to 5 months | 6.3 | 3.7 | N/A | 21.6 |
| 6 to 11 months | 9.1 | 5.4 | 7.3 | 27.0 |
| 1 year | 11 | 8.0 | 8.8 | 35.0 |
| 2 to 3 years | 15 | 9.2 | 6.2 | 21.4 |
| 4 to 8 years | 23 | 11.1 | 8.7 | 24.4 |
| 9 to 13 years | 42 | 13.9 | 6.9 | 23.8 |
| 14 to 18 years | 62 | 15.9 | 1.4 | 2.1 |
| Adults (19+) | 74 | 15.1 | 1.6 | 2.6 |
a Health Canada 2021
| Media | Median | 95th percentile | n | Reference |
|---|---|---|---|---|
| NAPS outdoor air PM2.5 | 0.874 ng/m3 | 3.032 ng/m3 | 969 | NAPS 2015 |
| NAPS outdoor air PM2.5 | 1.28 ng/m3 | 3.85 ng/m3 | 820 | NAPS 2016 |
| NAPS outdoor air PM2.5 | 1.65 ng/m3 | 6.03 ng/m3 | 1,333 | NAPS 2017 |
| NAPS outdoor air PM2.5 | 1.53 ng/m3 | 5.66 ng/m3 | 1,190 | NAPS 2018 |
| Outdoor air PM2.5 | 1.92 ng/m3 | 6.25 ng/m3 | 121 | Rasmussen et al. 2018 |
| Outdoor air PM2.5 | 0.723 ng/m3 | 4.83 ng/m3 | 610 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Outdoor air PM2.5 | 2.37 ng/m3 | 6.57 ng/m3 | 512 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Outdoor air PM2.5 | 2.16 ng/m3 | 9.47 ng/m3 | 125 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Outdoor air PM2.5 | 3.46 ng/m3 | 8.89 ng/m3 | 105 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Outdoor air PM2.5 | 0.727 ng/m3 | 3.19 ng/m3 | 55 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Outdoor air PM2.5 | 0.421 ng/m3 | 6.63 ng/m3 | 131 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Outdoor air PM2.5 | 0.78 to 2.0 ng/m3 | 1.5 to 67 ng/m3 | 230 | WBEA 2019 |
| Outdoor air PM2.5 | 0.81 to 2.2 ng/m3 | 6.3 to 10 ng/m3 | 302 | WBEA 2020 |
| Indoor air PM2.5 | 1.42 ng/m3 | 7.24 ng/m3 | 121 | Rasmussen et al. 2018 |
| Personal air PM2.5 | 0.64 ng/m3 | 6.97 ng/m3 | 78 | Rasmussen et al. 2018 |
| Indoor air PM2.5 | 1.04 ng/m3 | 6.51 ng/m3 | 595 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Indoor air PM2.5 | 5.53 ng/m3 | 15.97 ng/m3 | 133 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Indoor air PM2.5 | 2.50 ng/m3 | 12.38 ng/m3 | 79 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Personal air PM2.5, bus | 6.00 to 7.95 ng/m3 | 12.91 to 60.74 ng/m3 | 54 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Personal air PM2.5, subway | 4.17 to 18.52 ng/m3 | 9.25 to 67.25 ng/m3 | 54 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Indoor air PM2.5, private car | 6.07 to 10.48 ng/m3 | 11.78 to 14.54 ng/m3 | 22 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| Outdoor air PM2.5, private car | 7.32 to 15.62 ng/m3 | 26.27 to 101.12 ng/m3 | 22 | Personal communication, email from the WAQB, Health Canada, to the ESRAB, Health Canada, dated March 25, 2021; unreferenced |
| House dust | 2,100 μg/g | 4,000 μg/g | 818 | Rasmussen et al. 2022 |
| Infant formula, dairy-based, powder | 0.3 ppm (mean) | 0.42 ppm (maximum) | 52 | CFIA 2020 |
| Infant formula, soy-based, powder | 0.32 ppm (mean) | 0.54 ppm (maximum) | 7 | CFIA 2020 |
| Drinking waterNational survey in distribution systems | <5.0 μg/L | <5.0 μg/L | 97 | Tugulea 2016 |
| Soil, Ontario | 3,070 mg/kg | 4,939 mg/kg | 483 | Ontario [modified 2015] |
Abbreviations: n, number of observations/samples
| Age group | Mean intake (mg TiO2/kg bw/day) | Mean intake (mg Ti/kg bw/day) | 95th percentile intake (mg TiO2/kg bw/day) | 95th percentile intake (mg Ti/kg bw/day) |
|---|---|---|---|---|
| 12 weeks to 11 months | 0.03 to 2.9 | 0.02 to 1.7 | 0.1 to 9.9 | 0.06 to 5.9 |
| 12 months to 35 months | 0.6 to 6.0 | 0.36 to 3.6 | 1.9 to 27.5 | 1.1 to 16.5 |
| 3 years to 9 years old | 0.9 to 6.9 | 0.54 to 4.1 | 2.5 to 23.7 | 1.5 to 14.2 |
| 10 years to 17 years old | 0.6 to 3.6 | 0.36 to 2.1 | 1.6 to 13.2 | 0.96 to 7.9 |
| 18 to 64 years old | 0.3 to 3.8 | 0.18 to 2.3 | 1.2 to 9.5 | 0.72 to 5.7 |
| >65 years old | 0.2 to 2.8 | 0.12 to 1.7 | 0.9 to 7.1 | 0.54 to 4.3 |
| Age group (yr) | Black Lake | Fond du Lac | Stony Rapids | Wollaston Lake | Camsell Portageb | Uranium Cityc |
|---|---|---|---|---|---|---|
| 1 | 1.7 × 10-3 | 1.6 × 10-3 | 2.4 × 10-3 | 2.1 × 10-3 | 1.8 × 10-4 | 2.7 × 10-4 |
| 2 to 3 | 1.2 × 10-3 | 1.2 × 10-3 | 1.8 × 10-3 | 1.5 × 10-3 | 1.4 × 10-3 | 2.0 × 10-3 |
| 4 to 8 | 7.8 × 10-4 | 7.8 × 10-4 | 1.1 × 10-3 | 9.8 × 10-4 | 1.3 × 10-4 | 1.9 × 10-4 |
| 9 to 13 | 4.9 × 10-4 | 4.8 × 10-4 | 6.6 × 10-4 | 5.7 × 10-4 | 8.8 × 10-5 | 1.3 × 10-4 |
| 14 to 18 | 3.3 × 10-4 | 3.3 × 10-4 | 4.5 × 10-4 | 3.9 × 10-4 | 5.9 × 10-5 | 8.6 × 10-5 |
| Adult | 3.4 × 10-4 | 3.4 × 10-4 | 3.6 × 10-4 | 3.5 × 10-4 | 3.5 × 10-5 | 7.9 × 10-5 |
Abbreviation: yr, years
a Dietary intake estimates were derived based on the methodology presented in the EARMP 2017–2018 Human Health Risk Assessment (CanNorth 2018). Titanium occurrence data from 2015 to 2020 from the EARMP were combined, and average values were calculated by calculating the mean for commodities with less than 10 samples, while the 95% UCLM was derived for commodities with greater than or equal to 10 samples. Samples below the limit of detection were assumed to contain Ti content equal to the limit of detection. Consumption values from the EARMP 2017–2018 HHRA were used to derive intake estimates. Dietary intake = Σ[average concentration in commodity (mg/g) × daily consumption of commodity (g/day)/body weight (kg].
b Dietary intake estimates do not include contribution from birds (grouse) or small mammals (snowshoe hare), as no concentrations of titanium were measured in samples collected in Camsell Portage from 2015 to 2020 as part of the EARMP.
c Dietary intake estimates do not include contribution from small mammals (snowshoe hare), as no concentrations of titanium were measured in samples collected in Uranium City from 2015 to 2020 as part of the EARMP.
| Route of exposure | 0 to 5 monthsa humanmilk-fedb | 0 to 5 monthsa formula-fedc | 6 to 11 monthsd human milk-fedb | 6 to 11 monthsd formula-fedc | 1 year | 2 to 3 years | 4 to 8 years | 9 to 13 years | 14 to 18 years | Greater than or equal to 19 years |
|---|---|---|---|---|---|---|---|---|---|---|
| Ambient aird | 1.4 × 10-7 | 1.4 × 10-7 | 1.4 × 10-7 | 1.4 × 10-7 | 1.7 × 10-7 | 1.5 × 10-7 | 1.1 × 10-7 | 7.9 × 10-8 | 6.1 × 10-8 | 4.8 × 10-8 |
| Indoor aire | 7.2 × 10-7 | 7.2 × 10-7 | 7.3 × 10-7 | 7.3 × 10-7 | 8.9 × 10-7 | 7.5 × 10-7 | 5.9 × 10-7 | 4.1 × 10-7 | 3.1 × 10-7 | 2.5 × 10-7 |
| Drinking waterf | N/A | 6.6 × 10-4 | N/A | 4.2 × 10-4 | 1.6 × 10-4 | 1.4 × 10-4 | 1.2 × 10-4 | 8.8 × 10-5 | 8.8 × 10-5 | 1.0 × 10-4 |
| Food and beveragesg, h | 2.3 × 10-2 | 6.3 × 10-3 | 1.7 | 1.7 | 3.6 | 3.6 | 4.1 | 4.1 | 2.1 | 2.3 |
| Soili | N/A | N/A | 2.5 × 10-3 | 2.5 × 10-3 | 2.5 × 10-3 | 1.3 × 10-3 | 1.2 × 10-3 | 5.0 × 10-4 | 6.9 × 10-5 | 6.6 × 10-5 |
| Dustj | 7.2 × 10-3 | 7.2 × 10-3 | 6.2 × 10-3 | 6.2 × 10-3 | 6.7 × 10-3 | 3.0 × 10-3 | 2.2 × 10-3 | 1.2 × 10-3 | 7.1 × 10-5 | 7.4 × 10-5 |
| Total intakek (mg/kg bw/day) |
2.9 × 10-2 | 8.1 × 10-3 | 1.7 | 1.7 | 3.6 | 3.6 | 4.1 | 4.1 | 2.1 | 2.3 |
Abbreviation: N/A, not applicable
a It is assumed that no soil ingestion occurs due to typical caregiver practices.
b Human milk-fed infants are assumed to consume solely human milk for six months. Human milk-fed infants 0 to 5 months old are assumed to consume 744 mL of human milk per day, and human milk is assumed to be the only dietary source for infants under 6 months (Health Canada 2018). In the absence of Canadian human milk data, an arithmetic mean concentration of 0.240 μg/mL was calculated based on data from the scientific literature (Anderson 1992; Amarasiriwardena et al. 1997). As no information is available to suggest which of these studies is most representative of the typical range of titanium concentrations in the milk of women in Canada, the arithmetic mean concentration reported over studies in the US was used to estimate exposure to titanium from human milk in Canada. Infants 6 to 11 months old are assumed to consume 632 mL of human milk per day, in addition to some solid foods (Health Canada 2018).
c Exclusively formula-fed infants 0 to 5 months old are assumed to consume 826 mL of infant formula per day, and formula is assumed to be the only dietary source for infants under 6 months (Health Canada 2018). Concentration of titanium in infant formula is assumed to be 48 μg/L based on the measured concentration of 0.32 mg Ti/kg and a dilution of 9 g per 60 mL of water (CFIA 2020; Mead Johnson & Company, LLC 2020a, 2020b). Formula-fed infants 6 to 11 months old are assumed to consume 764 mL of formula per day (Health Canada 2018). Drinking water is used to reconstitute formula; therefore, infants 0 to 5 months and 6 to 11 months are assumed to consume 826 mL and 764 mL of drinking water per day, respectively.
d Intake estimated using the median 24-hour outdoor air sample PM2.5 of 1.9 × 10-3 µg/m3 (n=121) measured in Windsor, Ontario (Rasmussen et al. 2018). People living in Canada are assumed to spend 3 hours outdoors each day (Health Canada 1998).
e Intake estimated using the median 24-hour indoor air sample PM2.5 of 1.4 × 10-3 µg/m3 (n=121) measured in Windsor, Ontario (Rasmussen et al. 2018). People living in Canada are assumed to spend 21 hours indoors each day (Health Canada 1998).
f Intake estimated using the detection limit of 5 μg/L for titanium in drinking water from the national drinking water survey (n=97). The concentration of titanium was assumed to be equal to the detection limit (5 μg/L) for all samples of water from the drinking water distribution system where titanium was not detected at or above the detection limit (Tugulea 2016).
g For infants 0 to 5 months of age, dietary intake was estimated as mentioned in footnotes b and c. For infants 6 months and older, dietary exposure to titanium was sourced from EFSA’s re-evaluation of titanium dioxide (E171) as a food additive (EFSA 2021). Intake estimates were derived from food consumption data from 40 surveys in 23 European countries and the mean reported use levels provided by industry or analytical data from European member states. Where age groups were not comparable, the highest estimate was taken from the applicable age groups; details in Table A‑3.
h For the purposes of this exposure assessment, dietary intakes generated by EFSA (2021) using the upper mean exposure value from the refined non-brand-loyal consumer scenario are presented. Although some foods not captured by EFSA (2021) may contain titanium from background levels in the environment, foods available on the Canadian market, including those permitted to contain titanium-containing food additives, generally report levels of titanium that are orders of magnitude lower than those employed by EFSA (2021). Therefore, the EFSA (2021) exposure estimates are considered to be conservative, as dietary exposures for the general Canadian population are, overall, expected to be lower (personal communication, email from the FND, Health Canada, to the ESRAB, Health Canada, dated April 20, 2021; unreferenced).
i Intake estimated using the median titanium concentration of 3,070 mg/kg in soil from Ontario soil range (Ontario [modified 2015]). The titanium bioaccessibility factor from soil was not applied to the estimated intake, as bioaccessibility was assumed to be equal to oral bioavailability.
j Intake estimated using the median total titanium concentration of 2,100 μg/g measured in homes in Windsor, Ontario (n=818) (Rasmussen et al. 2022). The titanium bioaccessibility factor from dust was not applied to the estimated intake, as bioaccessibility was assumed to be equal to oral bioavailability.
Appendix B. Inhalation exposure estimates of titanium dioxide from the use of products available to consumers
Exposure estimates were derived for multiple age groups; however, only estimates for the age group with the highest exposure estimate are presented here. Exposure estimates were derived using the highest concentration (weight fraction) of titanium found per product type or scenario, unless otherwise noted. The concentration of titanium in products available to consumers was obtained through information notified to Health Canada under the Cosmetic Regulations, the internal SDS Search Tool (Health Canada 2019), DPD [modified 2022], LNHPD [modified 2024], and websites, as described in section 5.2.2.
Product amount, retention factor, and frequency of use in self-care product estimates were assumed based on internal defaults, unless otherwise noted (Health Canada 2020). The values used for product amount, exposure frequency (that is, frequency of use), and retention factors were developed through a process established for CMP assessments (Health Canada 2020). This process includes a review of the available data on product amount, frequency of use, and retention factors for self-care products, with respect to the comprehensiveness of the study or survey, the relevance of the data collected, and the type of information collected. The highest central tendency value from the studies with the highest quality rating is then selected for use in CMP assessments, and the underlying studies are cited.
Default inputs from the ConsExpo Web application and associated fact sheets (RIVM 2006, 2007, 2018, 2022) were used to estimate exposure from spray products unless otherwise noted in Table B-1 below. Exposure from the use of powder self-care products was estimated based on data from exposure studies, as described in section 5.2.2. Air concentrations generated for pouring of powder were estimated based on unit exposure values from the AEATF II solid pour study cited in the US EPA Science Review of the AEATF II solid pour (Powder & Granule) Human Exposure Monitoring Study (US EPA 2016). Product amounts and the exposure frequency of poured powders were derived from internal defaults or ConsExpo factsheets (RIVM 2018, 2022).
| Product | Exposure factors | Exposure (mg/m3) |
|---|---|---|
Self-care, leg foundation spray Sentinel scenario covering aerosol body moisturizer (cosmetic), aerosol sunless tanning product (cosmetic), aerosol body makeup (cosmetic), aerosol face makeup (cosmetic), aerosol fragrance (cosmetic), pump body spray (cosmetic), hair spray (cosmetic), nail polish spray (cosmetic), and sunscreen spray (NPD–NMI) |
From factsheet “Cosmetics; Deodorant cosmetics; Deodorant spray” (RIVM 2006) Age group: Adult 19+ Mean daily air concentration (mg/m3) = Event air concentration (mg/m3) × [exposure duration (min) × exposure frequency (/day) / 1,440 min/day] |
Event air concentration: 0.8 mg/m3 ean daily air concentration: |
| Self-care, temporary hair colour spray (cosmetic) |
From factsheet “Cosmetics; Hair care cosmetics; hair spray” Age group: Adult 19+ 4-hour average air concentration (mg/m3) = Event air concentration (mg/m3) × [exposure duration (min) / 240 min] Mean daily air concentration (mg/m3) = Event air concentration (mg/m3) × [exposure duration (min) × exposure frequency (/day) / 1,440 min/day] |
Event air concentration: 0.9 mg/m3 4-hour average air concentration: Mean daily air concentration: |
Self-care, face makeup Sentinel scenario covering powdered deodorant (cosmetic), powdered body moisturizer (cosmetic), powdered body makeup (cosmetic), other loose powdered makeup products (for example, blush, eyeshadow) (cosmetic), powdered face cleanser (cosmetic), and face makeup with SPF (NHP–NMI) |
Algorithm: Average talc study concentration: 1.36 mg/m3 (Anderson et al. 2017; Rasmussen et al. 2019; ECCC, HC 2021) Mean daily air concentration (mg/m3) = Event air concentration (mg/m3) × [exposure duration (min) × exposure frequency (/day) / 1,440 min/day] |
Event air concentration: Mean daily air concentration: |
Self-care, pouring powdered bath product Sentinel scenario covering the pouring of hair bleaching powder |
Algorithm: Unit exposure (8-hour TWA): 0.00545 mg/m3/lb ai handled (US EPA 2016) Mean daily air concentration (mg/m3) = 8-hour TWA air concentration (mg/m3) × (8 hours / 24 hours/day) × exposure frequency (/day) |
8-hour TWA air concentration: Mean daily air concentration: |
| Cleaning product, spray disinfectant (NPD–NMI) |
From factsheet “Cleaning and Washing; All-purpose cleaners; all-purpose cleaning spray” (RIVM 2018) Age group: Adult 19+ Mean daily air concentration (mg/m3) = Event air concentration (mg/m3) × [exposure duration (min) × exposure frequency (/day) / 1,440 min/day] |
Event air concentration: Mean daily air concentration: |
| Cleaning product, pouring powdered dish detergent | Algorithm: Unit exposure (8-hour TWA): 0.00545 mg/m3/lb ai handled (US EPA 2016)
|
8-hour TWA air concentration: Mean daily air concentration: |
Paints and coatings, aerosol spray paint can Sentinel scenario covering the application of wall paint using pneumatic sprayer, aerosol rust enamel spray, aerosol adhesives and sealants, spray ceiling and wall texture, spray floor coatings, and aerosol waterproofing spray |
From factsheet “Paint products; Spray painting; spray can” (RIVM 2007) Age group: Adult 19+ 4-hour average air concentration (mg/m3) = Event air concentration (mg/m3) × [exposure duration (min) / 240 min] Mean daily air concentration (mg/m3) = Event air concentration (mg/m3) × [exposure duration (min) × exposure frequency (/day) / 1,440min/day] |
Event air concentration: 4-hour average air concentration: Mean daily air concentration: |
| DIY product, pouring powdered tile grout | Algorithm: Unit exposure (8-hour TWA): 0.00545 mg/m3/lb ai handled (US EPA 2016) 4-hour average air concentration = 8-hour TWA air concentration (mg/m3) × (8 hours/4 hours) Mean daily air concentration (mg/m3) = 8-hour TWA air concentration (mg/m3) × (8 hours / 24 hours/day) × exposure frequency (/day) |
8-hour TWA air concentration: 4-hour average air concentration:3.6 × 10-2 mg/m3 Mean daily air concentration: |
Arts and crafts materials and toys, use of chalk Sentinel scenario covering the use of casting kits, coloured crayons, and powder paints |
Algorithm: Average study concentration: 0.393 mg/m3 i Mean daily air concentration (mg/m3) = Event air concentration (mg/m3) × [exposure duration (min) × exposure frequency (/day) / 1,440 min/day] |
Event air concentration: 0.012 mg/m3Mean daily air concentration:3.8 × 10-4 mg/m3 |
Abbreviations: NHP, natural health product; NMI, non-medicinal ingredient; NPD, non-prescription drug; SPF, sun protection factor
a Frequency of use is assumed to be daily for body makeup (professional judgment).
b Product amount (5.2 g) is adjusted by the ratio of leg surface area (5,970 cm2)/total body - head surface (17,530 cm2) area, as the product is intended for use on the legs (Health Canada 2020).
c Default spray duration is adjusted to account for adjusted product amount. Spray duration (minutes) = total product amount (g) / mass generation (g/second) × (1 minute/60 seconds)
d Airborne fraction was modified to 0.15 to account for the fact that 85% of deodorant is assumed to land on skin (RIVM 2006).
e The ConsExpo default for the inhalation cut-off diameter is 15 μm; this was refined to a cut-off of 10 μm for inhalable particles, which is the default often used by the Existing Substances Risk Assessment Bureau (Health Canada).
f Assuming that the product is sprayed away from the person, given that it is a product intended for use on the legs.
g Airborne fraction modified to 0.15 to account for 85% of hair spray assumed to land on head (RIVM 2006).
h Exposure time for powder face makeup is 5 minutes considering the duration of particle cloud, study sampling duration, formation of secondary exposure clouds and median time spent in the bathroom following a shower or bath (RIVM 2007; US EPA 2011; ECCC, HC 2021).
i Average study concentration for use of chalk is the average PM10 air concentration over 56 replicates from recent publications on the air concentration of PM from the use of chalk (Majumdar et al. 2012; Lin et al. 2015; Goel et al. 2017; Sekar et al. 2021).
j Frequency of use assumed to be daily for toys (professional judgment).
Appendix C. PBPK model for titanium and BE derivation
Figure C‑1. PBPK model for titanium and titanium dioxide
Long description
Figure C-1 is a schematic of the six-compartment PBPK model of titanium. The figure includes six compartments (gut, blood, liver, spleen, gonads, and the rest) and an excretion pathway (feces). Oral doses of titanium are represented by an arrow from the gut to the blood compartment, whereas I.V. doses of titanium are represented by an arrow directly to the blood compartment. From the blood compartment, titanium partitions to liver, spleen, gonads, and the rest of the body. The fraction absorbed from the gut to the blood compartment is shown alongside the arrow from the gut to the blood compartment. The kinetic rates are indicated alongside the arrows pointing from the gut to the blood compartment, from the blood to each compartment, from the liver to spleen comprtment, and the liver to excretion pathway (that is, feces).
Abbreviations: P.O., per oral; I.V., intravenous; Fabs, fraction absorbed; Floss, fraction lost; kabs, kinetic rate of absorption; kp’s, kinetic rates from the blood to the liver (l), spleen (s), gonads (g), or rest (r), or from the liver to spleen (ls) and for elimination from the liver to feces (el) (from Ramoju et al. [2020]).
| BE derivation stepa | Male rats | Female rats |
|---|---|---|
| POD (NOAEL), external dose (mg Ti/kg-bw/day) | 623 | 623 |
| BE-POD (NOAEL), steady-state blood concentration (mg Ti/L blood) | 2.15 | 1.61 |
| UF (interspecies, toxicodynamic) | 2.5 | 2.5 |
| BE-POD (mg Ti/L blood) | 0.86 | 0.65 |
| UF (intraspecies variation) | 10 | 10 |
| BE, blood concentration (mg Ti/L blood) | 0.0860 | 0.0646 |
| BE, blood concentration (μg Ti/L blood)b | 86 | 65 |
Abbreviations: BE, bioequivalent; L, litre; mg, milligram; NOAEL, no-observed-adverse-effect level; POD, point of departure; UF, uncertainty factor
a Model code for titanium pharmacokinetics in rat after oral administration (recoded in Berkeley Madonna; an original model by Heringa et al. [2016]) was obtained from the supplementary data of Ramoju et al. (2020).
b Multiplied by 1,000 to convert from mg/L to µg/L, rounded to 2 significant figures.