Titanium Dioxide

  • 20min
  • May. 2022
  • Supported by
    • SkinAlliance

WHAT IS TITANIUM DIOXIDE?

Titanium dioxide (TiO2) is widely used in a variety of products including some foods, paints, cosmetics, orthodontic composites, toothpastes and sunscreens. In cosmetics, TiO2 may be used either as a white pigment in its microcrystalline form only, or as an inorganic ultraviolet filter primarily in sunscreens, but also in some day creams, foundations, lip balms, etc.(1) TiO2 in its nanoparticle form (nano-TiO2) is now the only form used as a UV filter. Nano-TiO2 particles range from 1–100 nm in size and promote either dispersion or resistance to photoactivity.(2)

TiO2 particles can also vary in structure, and are found as both anatase and rutile crystal forms. Nano-TiO2 used in sunscreens is mostly of the rutile crystal structure or a rutile/anatase combination; they are rarely made up of the anatase structure alone.(2, 3)

Finally, nano-TiO2 is photoreactive with a resulting increase in reactive oxygen species (ROS) known to be implicated in cellular damage. This issue has been solved by coating nanoparticles with alumina or silica, to reduce the production of ROS. As coating improves the dispersion of TiO2 nanoparticles and their compatibility with other ingredients within sunscreen formulations, nano-TiO2 is always used in its coated form in cosmetics.(4)

WHERE DOES THE SAFETY CONCERN FOR NANO-TIO2 COME FROM?

The scientific evidence suggests that nano-TiO2 is an effective UV filter for the prevention of skin cancers and sunburn; however some concerns have been raised about its safety.(5)

Nano-TiO2 has been accused of penetrating dermal, respiratory or gastrointestinal barriers, and disseminating in the body, and therefore presenting a potential risk for the consumer.(6)

It is worth noting that many toxicological studies of nano-TiO2 use AEROXIDE P25 (Evonik, Germany), consisting mostly of nano-TiO2 less than 25 nm in size under their anatase form.(7) However, P25 is not used in cosmetics and P25 nano-TiO2 is not coated to reduce photoactivity.

This safety review concerning the use of nano-TiO2 in cosmetic products to provide UV protection is based on data published by the Scientific Committee on Consumer Safety (SCCS) and the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) and data available in the scientific literature since those opinions were published.(3, 6, 8)

DERMAL EXPOSURE TO TIO2 NANOPARTICLES

a. Absorption and distribution of nano-TiO2 particles into the skin is limited to the stratum corneum (9, 10)

More than 20 studies either in animals or in humans have investigated the dermal penetration of nano-TiO2 in healthy skin.(3) Most of these studies reported that nano-TiO2 remains on the skin after ‘real-life’ application of a sunscreen formulation, with only a small proportion of nano-TiO2 penetrating deeper in the stratum corneum. The nanoparticles do not reach the viable epidermis or dermis cells.(3)

Five studies demonstrated that nano-TiO2 contained in a sunscreen formulation did not penetrate compromised skin (stripped/dermabraded, sunburnt or psoriatic).(3) Even if nano-TiO2 penetrated deeper in the stratum corneum of psoriatic skin compared to healthy skin, it did not reach living cells in either psoriatic or healthy skin.(3)

b. Nano-TiO2 particles are considered to be a mild- or non-irritant to skin

There are currently no studies available that are relevant for assessing the acute dermal toxicity of nano-TiO2.(3)

Studies performed in guinea pigs and mice analysed by the SCCS and by the Therapeutic Goods Administration (TGA), Department of Health, Australia reported that nano-TiO2 is not a skin sensitiser.(3, 11-13)

c. Uncoated nano-TiO2 particles may cause phototoxicity in human skin cells

Six out of seven studies analysed reported that nano-TiO2 could induce the formation of reactive oxygen species (ROS), which may be a cause of cytotoxicity. These studies found that ROS induction in HaCaT cells was enhanced by UVA(14) and UVB(15) irradiation, but not by UVC irradiation(16), suggesting that nano-TiO2 leads to phototoxicity in human skin keratinocytes. The SCCS has stated that surface coating of nano-TiO2 is important to reduce its phototoxic effects.(3). It is worth noting that the coated form is always used in cosmetics.

d. Nano-TiO2 particles are not carcinogenic through dermal exposure

The Committee for Risk Assessment (RAC, European Chemicals Agency (ECHA)) considers that there is no evidence for TiO2 carcinogenicity for the dermal route.(17)

In 2014, the SCCS concluded that nano-TiO2 at a concentration up to 25%, as a UV-filter in sunscreens does not pose any risk of adverse effects in humans after application on healthy, intact or sunburnt skin.(3)

ORAL EXPOSURE TO NANO-TIO2

a. Nano-TiO2 particles absorption is negligible via the oral route

As some manufacturers can also use nano-TiO2 in UV-protecting lip balms that may be incidentally ingested, the potential ability of nano-TiO2 to penetrate oral and gastrointestinal mucosa has thus been investigated.

In a human model of the buccal mucosa, nano-TiO2 penetrated the epithelium, with most of the particles remaining in the upper third of the epithelial tissue.(18)

Another study administering a single dose of nano-TiO2 to 9 subjects reported that only negligible absorption occurred via the gastrointestinal tract after 2, 4, 24, and 48 h.(19)

This data demonstrates some nano-TiO2 penetration through the oral mucosa, but negligible absorption, if any, via the gastrointestinal tract after oral exposure to nano-TiO2 either in rats or in humans.(20-22)

b. Nano-TiO2 particles are distributed in the body

Two studies were analysed in a report from the French Institute for Industrial, Environment and Risks (INERIS).(23) One study reported that 2 weeks after a single administration of nano-TiO2 (25 and 80 nm, 5 g/kg bw), particles accumulated mainly in the liver, spleen, kidneys, and lungs in mice.(24) However the very high nano-TiO2 dose used in this study is not representative of the levels of human exposure.(25)

In contrast, a second study administering oral nano-TiO2 daily for 13 weeks reported no significant increase of titanium in liver, spleen, kidney and brain, and no dose-response relationship in rats.(21)

However, a more recent study using radiolabellednano-TiO2 reported distribution into rat liver, lungs, kidneys, brain, spleen, uterus and skeleton, 7 days after administration of a single dose of nano-TiO2 (~40 μg/kg/bw), even if the estimated amount absorbed was low at 0.09–0.98 ng/g depending on the organ.(22)

In conclusion, following oral intake, nano‐TiO2 can potentially permeate the gastrointestinal lining, but to a limited extent.

c. Nano-TiO2 has low rates of oral toxicity

Studies performed in rodents showed low oral acute toxicity of nano‐TiO2 except one study using very high doses. Repeated dose studies report that oral administration of nano-TiO2 leads to toxicity at various levels (central nervous system, kidney, spleen), but the doses used were far higher than those to which humans can be exposed to in the context of incidental oral exposure through cosmetics use.(26-32)

d. Nano-TiO2 particles do not have any carcinogenic potential via oral exposure

The few available data do not seem to indicate any potential carcinogenic activity associated with oral exposure to nano-TiO2.(23) The Committee for Risk Assessment (RAC) also considers that there is no experimental evidence to suggest that oral TiO2 may be carcinogenic.(17)

e.High-dose nano-Ti02 may affect reproduction

Studies performed in rats showed abnormal lung development and some neurotoxic effects in neonates after high doses of nano‐TiO2 administered to pregnant females.(33, 34)

INHALATION OF TIO2 NANOPARTICLES

a. Nano-TiO2 can be absorbed into the lungs via spray formulations but is not widely distributed

Considering the size of the nanoparticles, the SCCS has indicated that spray products could lead to lung exposure to nano-TiO2 by inhalation.(35) Studies have demonstrated that inhaled nanoparticles are mainly found in the upper airways (nose, mouth, pharynx, larynx and trachea), but can also reach the deeper lungs and deposit in the alveoli. Particles can be removed via coughing, mucociliary clearance and macrophages.(35, 36) Furthermore, inhaled nano-TiO2 particles can cross the lung barrier and travel throughout the body, although this phenomenon appears to be limited.(8, 22, 36-40)

b. Nano-TiO2 is associated with cytotoxicity in lung cells

Four studies analysed by Zhang et al. demonstrated that nano-TiO2 inhalation induces oxidative stress and/or apoptosis in the human lung cancer cell line A549 in vitro.(41)

In conclusion, cytotoxicity of nano‐TiO2 seems to be mediated by ROS production and enhanced by UVA or UVB irradiation in vitro.

c. There is no causal link observed between nano-TiO2 inhalation exposure and observed effects in acute and repeated-dose toxicity studies

The ANSES report evaluated several animal studies reporting the occurrence of nano-TiO2 toxicity at several levels (pulmonary, neurological, cardiovascular, liver, etc). First of all, these doses far exceed levels of human exposure, including cases of occupational exposure.(8)

Furthermore, most of the data focused on studies performed with the P25 form of nano-TiO2 (anatase 80–90%/rutile 10–20%) which is not used in cosmetic applications. Additionally, several biases were present in the studies, which limits their interpretation.

Finally, 8 studies assessed nano-TiO2 toxicological effects on humans exposed to nano-TiO2 by inhalation. Results suggested a possible pulmonary and cardiovascular effect. No conclusions could be drawn, as no causal link could be established between TiO2 inhalation exposure and the observed effects.

d. Nano-TiO2 particles may have some carcinogenic potential via inhalation in their P25 form

One study reported an increase in the incidence of lung tumours in rats exposed to repeated inhalation of nano-TiO2 (7.2–14.8 mg/m3 for 16 months).(42) Seven epidemiological studies in humans reported increased mortality rates due to lung cancer following inhalation of nano-TiO2, however no causal relationship could be established.(43-49)

We can conclude from the study of Heinrich et al.(42) that nano‐TiO2 (P25 as material tested) is a lung carcinogen in rats at a concentration resulting in pulmonary inflammation and altered clearance. This is consistent with the previous nano‐TiO2 classification as a suspected or possible carcinogen in humans by other organisations (International Agency for Research in Cancer (IARC), the National Institute for Occupational Safety and Health (NIOSH) and the Committee for Risk-Assessment-European Chemical Agency (RAC-ECHA)). Nevertheless, results obtained with the P25 form of nano‐TiO2 cannot be extrapolated to other forms of nano‐TiO2, and the concentrations used in these studies greatly exceeds the maximum human exposure.

e. Nano-TiO2 inhalation may affect reproduction

Nine studies, performed in mice (N=4) (50-53) or rats (N=5) (54-58) suggest a possible effect of pre- or peri-natal inhalation exposure to nano-TiO2. Studies in mice reported lung inflammation in gestating females, along with moderate neurobehavioral changes and gene expression changes in the liver in the offspring.

NANO-TIO2 USED IN COSMETICS ARE UNLIKELY TO BE GENOTOXIC

The genotoxicity of nano-TiO2, has been widely reported.(3, 8, 13) However the forms of nano-TiO2 used in these studies varied, with different shape, size, coating, surface reactivity, charge, and crystallinity, leading to inconsistent results.

Consequently, nano‐TiO2 can be considered as a weak genotoxic agent, as stated by national and international governmental organisations (ANSES, IARC, NIOSH and the UK Organisation for Economic Co-operation and Development (OECD)).

CONCLUSION:

Nano-TiO2 does not penetrate the skin beyond the surface layers to viable cells and does not reach the general circulation after application to either healthy or compromised skin. Nano-TiO2 from sunscreens does not present any health risks when applied on the skin at a concentration of up to 25%.

After oral exposure, nano-TiO2 absorption and toxicity seem to be limited. Incidental oral exposure to nano-TiO2 contained in lip balms is thus not expected to induce adverse health effects.

Finally, even if human data are sparse and inconsistent and, may include studies on the P25 form of nano-TiO2, lung inflammation has been reported in animal studies. Therefore, the SCCS does not recommend the use of nano-TiO2 in formulations that may lead to exposure of the lungs by inhalation, i.e., sprayable products and powders.

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