Plasticizer in children’s urine – are we about to lose another UV-filter?

Background

A key challenge in formulating sunscreens is deciding on the UV filter platform, as recently described by Hanay and Osterwalder ^[1] and also by Sohn et al ^[2]. Apart from the US, where the number of available UV filters is very limited, in Europe and the rest of the world there still seems to be a variety of options, despite intensive scrutiny over the last 25 years. For example, the discussion on endocrine disruptors and UV filters began with the publication of Schlumpf et al ^[3] in 2001, which resulted in 4-methylbenzylidene camphor being withdrawn from the market within two years. Until recently, many effective and powerful sunscreen formulations relied on the “remaining five” UV filters ^[1]:

UVB:

• Diethylhexyl Butamido Triazone (DBT)
• Ethylhexyl Salicylate (EHS)
• Ethylhexyl Triazone (EHT)

UVA: 

• Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (BEMT)
• Diethylamino Hydroxybenzoyl Hexyl Benzoate (DHHB)

By combining the “remaining five” UV filters DBT, EHS, EHT, BEMT and DHHB, it is possible to achieve an SPF 50 and a UVA-PF (in silico) of at least one third of the SPF with a total UV filter of 25 % and thus a good UV filter efficiency (SPF/% UV filter = 2). The sudden publicity surrounding the UVA filter DHHB at the beginning of this year is somehow reminiscent of the Schlumpf publication 23 years ago ^[3]. This column summarizes the developing situation chronologically and explains what the next steps could/should be to avoid the loss of another UV filter.

A short note in DER SPIEGEL (2024-02-10) as a trigger

On February 10, the German news magazine DER SPIEGEL published a short article entitled Poison in children’s urine ^[4]. The opening headline reads “how German toxicologists are investigating a whodunnit involving potentially banned substances – and how sunscreen products are being targeted” (Figure 1).

Toxicologists had discovered plasticizers in the blood and urine of kindergarten children. They found unusually high concentrations of mono-n-hexyl phthalate (MnHexP) in more than half of the 250 samples. The Institute for Prevention and Occupational Medicine of the German Social Accident Insurance has never detected such high levels in 20 years.

Mono-n-hexyl phthalate (MnHexP) is a degradation product of a plasticizer from the group of phthalates, which are considered to be particularly harmful to health because they can impair human fertility. The European Union (EU) has restricted the use of these substances, which has led to a reduction in their exposure. The recent discovery therefore did not fit into the picture of this success story.

It is not yet known where these higher levels of MnHexP really come from. The Federal Environment Agency has therefore begun its detailed detective work. An initial and preliminary suspicion points to sunscreen products, explains a toxicologist, but it is still too early to make any concrete statements about the product in question. And she warns against avoiding sunscreens. Sunscreens protect the skin. Not using them is harmful. This first DER SPIEGEL article concludes that certain products are now being targeted in the investigation to find the source of the elevated MnHexP levels.

Statement of German Federal Institute for Risk Assessment (BfR), (2024-02-23)

The BfR reacted very swiftly with a very comprehensive (20 pages) preliminary statement based on their knowledge and experience with similar phthalate plasticizers (summary translated by DeepL):

MnHexP in urine samples: Initial assessments of health effects ^[5]

According to an initial, preliminary assessment by the Federal Institute for Risk Assessment (BfR), the concentrations of the substance mono-n-hexyl phthalate (MnHexP) detected in urine samples do not give cause for increased concern. The detected concentrations are within a range that has also been detected for other phthalates in the context of serial tests. The BfR has classified the detected MnHexP values in terms of health on the basis of model calculations MnHexP can be formed in the body as a metabolic breakdown product (metabolite) from various phthalates. The cause of the elevated MnHexP levels in urine samples from adults and children is currently unclear. Intensive research into the source is being carried out by various parties. Various sources such as sunscreens or other consumer products are being discussed, and the BfR has also assessed whether sunscreens containing a UV filter potentially contaminated with DnHexP could pose a health risk. According to the current state of knowledge, adverse health effects from the use of such contaminated products are very unlikely. DnHexP itself is banned as an ingredient in cosmetic products, but it could be introduced into such products as an impurity in starting materials. To date, however, the BfR has no reliable information that cosmetic products containing UV filters are actually contaminated in relevant quantities with substances that could lead to the formation of MnHexP. Due to the reproductively harmful properties of both MnHexP and its possible precursors, these are classified as undesirable substances in the body. Their intake should be reduced as far as possible, which is why most phthalates are now subject to strict restrictions on use throughout Europe. It is therefore important to identify the source of the substance doi: https://doi.org/10.17590/20240223-160054-0© BfR | MnHexP | Statement of February 23, 2024 2 / 20This health risk assessment is preliminary. It was prepared on the basis of theoretical model calculations, which are subject to considerable uncertainties. Therefore, these calculations were prepared using particularly cautious assumptions. It can therefore be assumed that possible risks have been overestimated rather than underestimated. A further uncertainty is that there are as yet no limit values or guide values for MnHexP or the possible starting material DnHexP. Information on the health effects of phthalates with a similar chemical structure, for which corresponding values exist, was therefore used for the preliminary assessment. As an additional safety margin, the BfR has assumed that the two substances mentioned could be up to five times more potent than the phthalate with the currently lowest limit/guideline values (di-n-butyl phthalate, DnBuP). The BfR calculations only show that the current lowest limit/guideline values are exceeded in a very small number of cases. These are in the same order of magnitude as has been shown for other phthalates in the recent past, for example in the GerES-V study by the Federal Environment Agency. Phthalates are chemical compounds that are mainly used as plasticizers in plastics such as PVC. However, the phthalates are not firmly bound in the respective plastics, but can be released from them. Because phthalates are produced and used in large quantities, they can be detected almost everywhere in the environment (soil, water, air).

The BfR statement also explains where MnHexP originates from. It is the primary metabolite of the Phthalate-Diester (Figure 2, in German)

More Details from DER SPIEGEL (2024-02-27) point to DHHB from BASF

Two weeks after the first short article, DER SPIEGEL published a more detailed story, now with the suspicion that DHHB might be the culprit (translated by DeepL):

BASF has apparently known about harmful contamination in sun creams for years ^[6].

German authorities have found evidence of a harmful substance in urine samples. A UV filter from BASF is suspected to be the source. Experts are debating how dangerous the exposure is.

The list of ingredients in sun creams reads like a list of unpronounceable words. The third or fourth ingredient is often a substance with the abbreviation DHHB, diethylamino hydroxybenzoyl hexyl benzoate. This is a UV filter that the chemical giant BASF advertises as “ideal for long-lasting sun protection”. It even claims to have an “anti-ageing effect”.

The company is reluctant to talk about another side of DHHB.

According to SPIEGEL research, the UV filter may be responsible for a conspicuous level of harmful substances in many people in Germany, which the Federal Environment Agency (Uba) pointed out at the beginning of February. Urine samples were found to contain elevated levels of the substance MnHexP, which is produced when the harmful plasticizer DnHexP is broken down in the body. This plasticizer is a by-product of the production of the UV filter DHHB. However, because it is identified as a substance of very high concern and classified as toxic to reproduction, its use is largely banned in the European Union.

Trail leads to a patent

A patent specification with the number EP4110/54A1, filed in February 2021, provides a further indication of the source of the banned substance. It mentions that DnHexP is produced “as a byproduct” during the production of DHHB. It also states that the content should be kept as low as possible, as the substance could “impair fertility and harm the unborn child”. BASF has applied for the patent. The Ludwigshafen-based company has therefore been aware of possible contamination with the substance for at least three years.

However, when asked, the company merely stated that “no connection between sun protection and urine values can be derived from the available data”. The company only markets products “that meet the strict criteria for quality, safety and health”. BASF also points out that the company is not the sole manufacturer of the UV filter DHHB. “Based on the available data, it is currently not Suspected plasticizer in sunscreen: BASF has known about harmful substance in UV filter for years. It is not yet known which products or sources are responsible for the occurrence of the substance in the samples. Various possible sources are being discussed and investigated.”

BASF Patent [7]:

The BASF describes a procedure to reduce the by-product di-n-hexylphthalate (Figure 3). A patent of course says nothing about how much of this by-product is contained in the UV filter DHHB, which is currently produced and sold by BASF. Only an analysis of the UV filter and the sunscreens produced with DHHB can provide this information.

Investigations of the Food monitoring and animal health investigation office Karlsruhe (CVUA) (2024-03-04)

Prohibited plasticizer as a contaminant in sunscreens? – First test results ^[8].
Cosmetics team of the CVUA Karlsruhe

The press reports on the findings of the metabolite mono-n-hexyl phthalate (MnHexP) in urine samples from children and adults are currently coming thick and fast. Sunscreens were discussed relatively quickly as a possible source, which are said to contain the alleged precursor, the reprotoxic plasticizer di-n-hexyl phthalate (DnHexP). The Chemical and Veterinary Investigation Office Karlsruhe (CVUA) then examined 57 sun protection products from 2020 to 2023 for their DnHexP content. A possible connection with the UV filter DHHB was also scrutinized. DnHexP was actually detected in some of the samples, with concentrations ranging from 0.3 to 16 mg/kg (detection limit of 0.2 mg/kg). The CVUA experts recommend continuing to pay close attention to protection against harmful UV radiation.

In the years 2020 to 2023, the CVUA Karlsruhe only tested a small selection of cosmetic products for phthalates, including DnHexP, using HPLC-DAD. Sunscreens have not been the focus before.

Using this method, 57 different sunscreens from the years 2020 (11 samples), 2021 (6 samples) and 2023 (40 samples) were initially analyzed in individual determinations. The contents of the UV filters used in the products were known from the regular monitoring of sunscreens. DnHexP was not detectable in 36 of 57 sunscreen products tested (< 0.2 mg/kg). Of these, 17 products did not contain the UV filter DHHB, which is suspected as a possible source. DnHexP was also not detectable in 19 samples with DHHB contents between 1.0 and 8.4 % (see Figure 4, 5).

Statement by the Consumer Advice Center (Verbraucherzentrale) (2024-03-14)

The consumer advice center warns against the use of sunscreens containing DHHB ^[9]:

As the CVUA Karlsruhe test report did not publish which sunscreens were contaminated with the plasticizer and which were not, the only precautionary recommendation at present is to avoid sunscreens containing the ingredient diethylamino hydroxybenzoyl hexyl benzoate (DHHB) altogether and to avoid other cosmetic products containing this UV filter.

Be careful with sunscreens containing the UV filter DHHB (diethylamino hydroxybenzoyl hexyl benzoate): This UV filter is partially contaminated with a plasticizer, as studies by the Chemical and Veterinary Investigation Office (CVUA) Karlsruhe show. Of 40 sun creams with DHHB, 21 contained a banned phthalate plasticizer that can damage the endocrine system and whose degradation product was detected in the urine of children and adults.

Preliminary Conclusion

This recent case of traces of plasticizers in children’s urine tells us, or confirms, a great deal. We live in a world of ubiquitous, unwanted traces of chemicals around us and within us. What is special in this case, of course, is the rapid increase in the concentration in the children’s urine and thus also previously in their blood. What we don’t yet know is the exact route and circumstances of how MnHexP got there. But it looks like the tools to find out are in place.

One question I’ve been asking myself is whether or not MnHexP is readily able to penetrate human skin. The physical data we need to verify this is the molecular weight (250.29) and the partition coefficient between octanol and water, Log Po/w (4.2) ^[10].

The “500 Dalton rule” answers this question ^[11]. 100% permeation of MnHexP through normal skin is expected (Figure 6)

As a preliminary conclusion, based on my assessment of the currently available evidence, there is no justification for us to lose yet another UV filter, especially a UVA filter. Rather, the use of certain sunscreens by certain groups should be assessed using a risk management approach.

A risk management approach is needed

Whatever the final findings, we should already be thinking about what we are going to do with them. While Brian Diffey argues for a risk management approach to sun protection ^[12], i.e. dealing with the carcinogenic UV radiation, I equally argue for a risk management approach when it comes to the use of sunscreens (Figure 7, in red).

Risk management is the process that leads to a choice between alternative courses of action and determines the priorities and strategies for implementation. The process of risk management can be broadly divided into a determination and an assessment, i.e. a scientific and a social activity (Figure 7). We discussed this last year in a Sweep the Sun column entitled Are Sunscreens Safe? ^[13].

People perceive risk differently depending on how well they know and understand the risk in question, and also on how they might personally suffer from the consequences of the risk. Diffey spoke exclusively about the risk of UV exposure, but with discussions about the efficacy and safety of sunscreens, risk management takes on a new dimension. Sunscreens, which are designed to reduce the risk of UV radiation, have now themselves become the subject of risk management.

Stay tuned!

References

1. Hanay C, Osterwalder U. Challenges in Formulating Sunscreen Products. Curr Probl Dermatol. 2021;55:93-111. doi: 10.1159/000517655. Epub 2021 Oct 25. PMID: 34698
2. Sohn M, Krus S, Schnyder M, Acker S, Petersen-Thiery M, Pawlowski S, Herzog B, How to Overcome the New Challenges in Sun Care, SOFW Journal 146(7,8), 2020, 2-10
3. Schlumpf M, Cotton B, Conscience M, Haller V, Steinmann B, Lichtensteiger W. In vitro and in vivo estrogenicity of UV screens. Environ Health Perspect. 2001 Mar;109(3):239-44. doi: 10.1289/ehp.01109239.
4. Schlak Martin, Poison in Children’s Urine (translated from German), DER SPIEGEL, Nr. 7, 2024-02-10
5. Bundesinstitut für Risikobewertung, 2024. MnHexP in Urinproben: Erste Einschätzungen zu gesundheitlichen Wirkungen: Stellungnahme Nr. 011/2024 des BfR vom 23. Februar 2024, BfR-Stellungnahmen. Bundesinsitut für Risikobewertung.  https://doi.org/10.17590/20240223-160054-0
6. Schlak Martin, BASF has apparently known about harmful contamination in sun creams for years (translated from German), DER SPIEGEL Nr. 10, 2024-02-27
7. WO 2023/242181 A1, METHOD FOR OBTAINING CRYSTALLINE DIETHYLAMINO HYDROXYBENZOYL HEXYL BENZOATE, Intl Patent BASF SE, Priority date (EP): 2022-06-17
8. CVUA Baden-Würtenberg, Karlsruhe, Prohibited plasticizer as a contaminant in sunscreens? – First test results (translated from German), https://www.ua-bw.de/pub/beitrag.asp?subid=2&Thema_ID=4&ID=3940&lang=DE&Pdf=No
9. Verbraucherzentrale, Sonnencreme: Worauf Sie achten sollten, https://www.verbraucherzentrale.de/wissen/umwelt-haushalt/produkte/sonnencreme-worauf-sie-achten-sollten-13710, 2024-03-11 accessed 2024-03-18
10. Monohexyl Phthalate,  COMPOUND SUMMARY, NIH, National Library of Medicine, PubChem https://pubchem.ncbi.nlm.nih.gov/compound/Monohexyl-Phthalate accessed 2024-03-17 1.
11. Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. 2000;9(3):165–9
12. Diffey B, Sun Protection: A Risk Management Approach, IOP Publishing Ltd, Institute of Physics Publishing, Bristol, UK (2017).
13. Osterwalder Uli, Are sunscreens safe? Sweep the Sun, EURO-COSMETICS Newsletter, 2023-04, https://www.eurocosmetics-mag.com/sweep-the-sun/