6. Are sunscreens using zinc oxide nanoparticles safe?

6. Are sunscreens using zinc oxide nanoparticles safe?

Safety evaluation (including calculation of the MoS)

The data provided, and as present in the literature, indicate that ZnO nanoparticles do not penetrate through the skin. However, some minimal absorption of zinc was demonstrated. Although the zinc was determined by methods which do not discriminate between particulate and solubilized forms, considering the dissolution rate of ZnO, it is likely that this was in the form of solubilized zinc ion. This conclusion is based on the weight of evidence from the available studies so far which suggest that only a small fraction of the nano- sized ZnO is likely to be solubilized in a formulation, and possibly when in contact with the skin, and a part of this solubilized fraction may subsequently be absorbed. The maximum solubility is estimated to be around 50 mg/L, depending on the solvent/medium under static equilibrium conditions. However, in view of the dissolution rate of ZnO, any translocating ZnO nanoparticles will also be completely solubilized due to the non-static conditions in the biological environment (see section 3.1.6). Thus, until proven otherwise, it is assumed that any transdermal penetration following application the nano-ZnO containing cosmetic product is that of Zn ions released from the ZnO nanoparticles.

As internal exposure is likely to be to ionic Zn, the safety considerations as indicated below in the EU Risk Assessment Report on Zinc Oxide (2004) (Reference 44, sub III) are relevant:

The total database available indicates that skin-bound zinc may not become systemically available in a way that it results in high peak levels of zinc in serum, but rather in a more gradual way. Given the efficient homeostatic mechanisms of mammals to maintain the total body zinc and the physiologically required levels of zinc in the various tissues constant, the anticipated slow release of zinc from the skin is not expected to disturb the homeostatic zinc balance of the body. By expert judgement, based on the aforementioned considerations, the default for dermal absorption of solutions or suspensions of zinc or zinc compounds is therefore chosen to be 2%. Based on the physical appearance, for dust exposure to zinc or zinc compounds a 10-fold lower default value of 0.2% is chosen in the risk assessment.

For sunscreen containing 10% zinc oxide the following exposure assessment was performed:

By an application of 9 g sunscreen/event, 3 events/day during 18 days/year the exposure will be 1,332 mg sunscreen/day, being 107 mg Zn2+/day. Assuming a dermal absorption of 2% the uptake is estimated to be 2.14 mg Zn2+/ day.

An NOAEL of 50 mg Zn2+/day was derived from a 10-week oral study with human volunteers and was used as a starting point for the risk characterization for repeated dose toxicity. This NOAEL of 50 mg Zn2+/day results in an internal NOAEL of 10 mg Zn2+/day by correction for oral absorption (20%; worst case, because of the homeostasis the relative absorption will be smaller by excess of Zn2+-intake). Given that this study was with women (the most sensitive population in zinc supplementation studies), and that in women clinical signs begin to appear only at a dose three times this NOAEL, a minimal MOS of 1 is considered sufficient when comparing the human NOAEL with the exposure levels for workers/consumers/general population.

The MOS between this internal NOAEL and the internal exposure as a result of exposure to sunscreen formulations is 5, which is a factor of 5 larger than the minimal MOS.

The SCCS agrees with the NOAEL indicated in the RAR statement. Therefore, this information is used together with the data from the absorption study provided in the dossier and exposure assumptions from the SCCS Notes of Guidance for the risk assessment of zinc oxide nanoparticles in sun screens as follows:

Calculation of the margin of safety for ZnO (nano)

(See section 3.1.16 for the range of nano-ZnO covered by this opinion)

Amount of sunscreen applied*

18,000 mg

Maximum concentration of ZnO

25%

Absorption through the skin

0.03% (Reference: 36)

Amount absorbed/day

(18,000 × 25%/100 × 0.03%/100)

1.35 mg

Typical body weight of human

60 kg

Systemic exposure dose

(1.35 mg/60 kg)

0.0225 mg/kg bw/d

No Observed Adverse Effect Level NOAEL

(oral, human, sensitive subpopulation)**

0.166 mg/kg bw/d

Margin of Safety

NOAEL/SED

= 7.4

* Standard amount as indicated in the SCCS Notes of Guidance for the testing of cosmetic ingredients and their safety evaluation SCCS/1416/11

** The internal NOAEL for ZnO is 10 mg Zn2+/day = 10/60= 0.166 mg /kg bw per day (Reference 44, sub III)

The calculation of the exposure via sun protection products to ZnO nanoparticles assuming Zn2+ uptake results in a MoS of 7.4. Given that the NOAEL is derived from a study on women (the most sensitive population in zinc supplementation studies), and that in women clinical signs begin to appear only at a dose three times this NOAEL, a minimal MOS of 1 is considered sufficient when comparing the human NOAEL with the exposure levels for workers/consumers/general population (Reference 44, sub III).

Calculation of the Margin of Safety for Lip products

According to the SCCS Notes of Guidance for the testing of cosmetic ingredients and their safety evaluation (SCCS/1416/11) the daily exposure to lipstick/lipproducts is 0.9 mg/kg/d.

Exposure dose (0.9 x 25%)

0.225 mg/kg bw/day.

No Observed Adverse Effect Level NOAEL

(oral, human)*

0.83 mg/kg bw/d

Margin of Safety

NOAEL/ED**

= 3.7

* The NOAEL for ZnO is 50 mg Zn2+/day = 50/60= 0.83 mg /kg bw per day (Reference 44, sub III)

** Since route to route extrapolation is not needed, the (external) NOAEL is compared to the (external) exposure dose

It is expected that the exposure to lipstick/lip products that contain high SPF factors (eg ZnO nanomaterial) is less than the exposure to ‘regular’ lipstick/lip products. Typically, these products are used only in specific time frames, e.g. during outdoor holidays. Therefore 0.9 mg/kg bw/d is considered a conservative value.

The calculation of the exposure via lip products to ZnO nanoparticles assuming Zn2+ uptake results in a MoS of 3.7 (with a minimal MOS of 1 required, see above).

Risk assessment of nanomaterials still has some issues to adress. At present, there are still certain gaps in the knowledge, for instance on the behaviour of nanoparticles in the test medium or in the animals. This leads to uncertainties on whether the particles remain free and hence able to reach the biological target sites and interact with various moieties, or they agglomerate/ aggregate and become less biologically available. There are also limitations in the validity of some of the tests used as they were developed for conventional (soluble) chemicals and not for nanoparticles. However, clear positive toxic responses in some of these tests clearly indicate a potential for risk to humans.

1. Does the SCCS consider zinc oxide in its nano-form safe for use as a UV-filter with a concentration up to 25% in cosmetic products taking into account the scientific data provided?

With regard to applications resulting in dermal exposure

From the available information, there is no indication for penetration of ZnO nanoparticles through the skin. In one study it was shown that Zn from ZnO nanoparticles in a tested sunscreen formulation made a minor contribution to the blood Zn pool of human volunteers. This shows that some Zn was absorbed from the sunscreen, although it was not known whether this was absorbed in nanoparticulate form or as solubilized Zn ions. Considering the dissolution of ZnO, it is most likely that the zinc was absorbed in ionic form. The overall weight of evidence therefore suggests that a very small proportion of Zn ions released from the ZnO nanoparticles may be available for systemic exposure when applied dermally.

With regard to applications resulting in other routes of exposure

Oral exposure

In one exploratory study in mice, systemic availability of Zn was indicated after a single oral exposure. However, no differences were observed between ZnO administered as nanoscale or microscale particles. It is likely that absorbed Zn in the GI-tract was in the dissolved ionic form. In view of the data provided, oral exposure of nano-ZnO via applications of nano-ZnO as a cosmetic ingredient in sunscreens should be considered to be of a similar risk to micron -sized ZnO as previously evaluated in the RAR. The NOAEL for oral intake of ZnO is 50 mg /bw day (Reference 44, sub III). The oral exposure to ZnO nanoparticles as cosmetic ingredient in sunscreens is limited to accidental ingestion of small fractions of lip products and sun protection products and can be considered to be low.

Inhalation exposure

Upon inhalation of ZnO nanoparticles, serious local effects in the lung were observed. Even if this may be due to the solubilized Zn ions, the effects are a direct result of the exposure to the ZnO nanoparticles. Therefore, the SCCS is of the opinion that, on the basis of available information, the use of ZnO nanoparticles in spray products cannot be considered safe.

Overall conclusions

In summary, the evidence presented in this submission and the available literature showed that:

• There is no evidence for the absorption of ZnO nanoparticles through skin and via the oral route. Even if there was any dermal and/or oral absorption of ZnO nanoparticles, continuous dissolution of zinc ions would lead to complete solubilization of the particles in the biological environment. In the MoS calculation, the calculation of the exposure to ZnO nanoparticles assuming Zn2+ uptake results in acceptable MoSs for both the oral and dermal routes.
• Nano ZnO-containing cosmetic formulations are likely to contain a small proportion of solubilized zinc, a further small proportion of which may be absorbed through skin and other routes. The rate and amount of the absorbed zinc is, however, likely to be insignificantly small compared to the large zinc pool already present in the body.
• Although the current evidence in relation to potenial genotoxicity of ZnO is not conclusive, the use of nano ZnO in cosmetic products should not pose a risk to the consumer in the absence of a significant systemic exposure.
• Based on the parameters described in the dossier, the different particle sizes, surface modifications, and crystalline structures and morphologies investigated do not significantly alter the uptake, bioavailability and overall safety profile.
• The different typical formulations as described in this submission also do not change the overall safety profile of the tested ZnO nanoparticles.

In summary, it is concluded on the basis of available evidence that the use of ZnO nanoparticles with the characteristics as indicated below, at a concentration up to 25% as a UV-filter in sunscreens, can be considered not to pose a risk of adverse effects in humans after dermal application. This does not apply to other applications that might lead to inhalation exposure to ZnO nanoparticles (such as sprayable products). Also, this assessment only applies to ZnO nanoparticles that are included in this dossier, or are similar materials that have the following characteristics:

• ZnO nanoparticles of purity ≥99%, with wurtzite crystalline structure and physical appearance as described in the dossier, i.e. clusters that are rod-like, star-like and/or isometric shapes.
• ZnO nanoparticles with a median diameter (D50: 50% of the number below this diameter) of the particle number size distribution between 30 nm and 55 nm, and the D1 (1% below this size) above 20 nm.
• ZnO nanoparticles that are either uncoated, or coated with triethoxycaprylylsilane, dimethicone, dimethoxydiphenylsilanetriethoxycaprylylsilane cross-polymer, or octyl triethoxy silane.
• ZnO nanoparticles that have a comparable solubility to that reported in the dossier, i.e. below 50 mg/L (approximately the maximum solubility of the ZnO nanomaterials for which data are provided in the dossier).

Some tests were performed with a nano-ZnO material with a purity of ≥96% as indicated in the submission. However, data on the purity was not provided in the physico-chemical characterization section (3.1.4), and was also not provided in the various study reports cited although in one report a content of 100% was indicated.

It is worth highlighting that this opinion has considered the small proportion of the absorbed Zn following dermal application of nano ZnO to most likely be a solubilised ionic form. This is in consideration of the solubility and dissolution aspects of ZnO described in section 3.1.6. However, if any new evidence emerges in the future to show that the translocating species were in the form of insoluble and potentially persistent nanoparticles, then the SCCS may consider revising the safety assessment of nano ZnO.

It should also be noted that the risk assessment of nanomaterials is currently evolving. In particular, the toxicokinetics aspects have not yet been fully explored in the context of nanoparticles (e.g. the size dependency). Also, long term stability of the coatings remains unclear. At the moment, testing of nanomaterials and the present assessment, are both based on the methodologies developed for substances in non-nano form, and the currently available knowledge on properties, behavior and effects of nanomaterials. Therefore this assessment is not intended to provide a blue-print for future assessments of other nanomaterials, where depending on the developments in methodological risk assessment approaches and nano-specific testing requirements, additional/different data may be required and/or requested on a case-by-case basis.

2. Does the SCCS confirm that zinc oxide in its non-nano form is safe for use as a UV-filter with a concentration up to 25% as stated in the SCCP clarification (SCCP/1215/09)?

The SCCS considers that the use of larger (non-nano) forms of ZnO as a UV-filter with a concentration up to 25%, as stated in the SCCP clarification (SCCP/1215/09), is safe and is not of any additional safety concern compared to the nano-forms assessed in this Opinion. This is in view of the following:

• When compared in terms of solubility, micro-sized ZnO has been shown to be less soluble (in water), and equally soluble (in tissue culture medium) compared to nano-ZnO.
• Experimental evidence shows that both nano and non-nano particulate forms of ZnO are not absorbed through the skin. Also on a theoretical ground, larger sized (non-nano) particles of ZnO are less likely to be absorbed through the skin than the nano-forms.
• As far as evaluated in the toxicity testing, micro-sized ZnO has been shown to induce either similar toxic effects (in terms of general toxicity, lung toxicity after inhalation, uptake from gastroIntestinal-tract, serum liver enzyme presence) or lower toxic effects (in terms of genotoxicity, liver histopathology) when compared to nano-sized ZnO. No toxic effects were observed at similar doses in a human volunteer inhalation study for both nano-sized ZnO (40 nm) and fine ZnO (291 nm).

Thus the calculation of MoS for nano-sized ZnO for use as a cosmetic ingredient in sunscreen formulations can also be used for the non-nano form of ZnO.

The SCCS would like to point out that a re-evaluation may be needed in the case of use of other specific coatings or specific absorption enhancers in the formulation, which can promote the dermal penetration of ZnO particles (nano or non-nano), or indications of dermal absorption after long term use of nano ZnO containing formulations.

3. And/or does the SCCS have any further scientific concern with regard to the use of zinc oxide in cosmetic products?

ZnO is also used as a colorant in cosmetic products. In view of the similar toxicity of both nano-sized and fine ZnO, it is considered that ZnO is safe when used as colorant in cosmetics for dermal application. However, no information is available on whether and at what concentrations ZnO is used in other cosmetic products that may lead to oral or inhalation exposure. The MoS for such uses is uncertain.

In view of the lung inflammation induced by ZnO particles after inhalation exposure, the use of ZnO in cosmetic products which may result in inhalation is of concern.

Any cosmetic products containing ZnO particles (nano or non-nano) with coatings that can promote dermal penetration will also be of concern.