Oxybenzone

From Wikipedia, the free encyclopedia
Jump to: navigation, search
"Benzone" redirects here. It is not to be confused with benzene.
Oxybenzone[1]
Oxybenzone
Identifiers
CAS number 131-57-7 YesY
PubChem 4632
ChemSpider 4471 YesY
UNII 95OOS7VE0Y YesY
DrugBank DB01428
KEGG D05309 YesY
ChEBI CHEBI:34283 N
ChEMBL CHEMBL1625 YesY
Jmol-3D images Image 1
Properties
Molecular formula C14H12O3
Molar mass 228.24 g mol−1
Density 1.20 g cm−3[2]
Melting point 62 to 65 °C (144 to 149 °F; 335 to 338 K)
Boiling point 224 to 227 °C (435 to 441 °F; 497 to 500 K)
Acidity (pKa) 7.6 (H2O)[3]
Hazards[2]
Flash point 140.5 °C (284.9 °F; 413.6 K)
LD50 >12800 mg/kg (oral in rats)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Oxybenzone or benzophenone-3 (trade names Eusolex 4360, Escalol 567, KAHSCREEN BZ-3) is an organic compound used in sunscreens. The molecule was first synthesized in 1906, but the method for commercial production was not patented until 1975.[4] It forms colorless crystals that are readily soluble in most organic solvents. Oxybenzone belongs to the class of aromatic ketones known as benzophenones. It provides broad-spectrum ultraviolet coverage, including UVB and short-wave UVA rays. As a photoprotective agent, it has an absorption profile spanning from 270 to 350 nm with absorption peaks at 288 and 350 nm.[5] It is one of the most widely used organic UVA filters in sunscreens today.[5] It is also found in nail polish, fragrances, hairspray, and cosmetics as a photostabilizer. Despite its photoprotective qualities, much controversy surrounds oxybenzone because of its possible hormonal and photoallergenic effects, leading many countries to regulate its use.

Structure and electronic structure[edit]

Being a conjugated molecule, oxybenzone absorbs at low energies.[6] As in related compounds, the hydroxyl group is hydrogen bonded to the ketone.[7] This interaction contributes to oxybenzone's light-absorption properties. At low temperatures, however, it is possible to observe both the phosphorescence and the triplet-triplet absorption spectrum. At 175 K the triplet lifetime is only 24 ns. The short lifetime has been attributed to an extremely fast and reversible excited-state intramolecular hydrogen transfer between the oxygen of the C=O and the OH. This pathway provides an efficient energy-wasting pathway that is responsible for the absorption capabilities.[8]

Production[edit]

Although trace amounts occur naturally in some plants, oxybenzone is mainly a manufactured chemical. The US lists oxybenzone as a High Production Volume (HPV) chemical, meaning it was produced in or imported into the U.S. in >1 million pounds (>450,000 tonnes) in 1990 and/or 1994.[4]

Methods of manufacturing[edit]

Oxybenzone is manufactured in several different countries including: Israel, The United Kingdom, France, Germany, Taiwan, Japan, and China.[4]

One method of manufacturing oxybenzone is to condense benzoic acid with resorcinol monomethyl ether by heating the solution in the presence of ZnCl2 and polyphosphoric acid.[4] Another method of production utilizes a Friedel-Crafts reaction of benzoyl chloride with 3-hydroxyanisole. The product of this reaction is subsequently recrystallized from a solution of water and methanol and then dried.[4]

Major uses[edit]

Oxybenzone is used in plastics as an ultraviolet light absorber and stabilizer.[4] It is used, along with other benzophenones, in sunscreens, hair sprays, and cosmetics because they help prevent potential damage from sunlight exposure. It is also found, in concentrations up to 1%, in nail polishes.[4] Oxybenzone can also be used as a photostabilizer for synthetic resins.[4]

Safety and controversy[edit]

There is much debate on whether oxybenzone poses a threat to the population as an endocrine disruptor.[5] The safety of oxybenzone is difficult to assess, particularly in products such as sunscreen.[5] Sunscreen is typically applied topically, but many studies that claim oxybenzone is hazardous were performed by injecting the compound directly into the test animal. Studies have shown that by topical application of sunscreen, oxybenzone is absorbed through the skin and excreted in urine.[9] Up to 1–2% of the applied amount is estimated to be absorbed into the body.[10] The method of administration discrepancy is the biggest issue when analyzing this data. A secondary debate arises because most of the studies done so far have tested zebrafish, rats, or pig skin rather than humans. This adds to the complication of extrapolating these studies to assess risks associated with human use.

The outstanding controversy over the potential adverse effects of oxybenzone on the human body is namely between the Environmental Working Group (EWG) and researchers who claim that that oxybenzone's impact is ultimately insignificant. According to EWG research, 84% of over 900 sunscreen products brands ineffectively protect against harmful rays or contain chemicals like oxybenzone.[11] Sunscreen typically includes a combination of three to six active ingredients such as oxybenzone, avobenzone, octisalate, octocrylene, homosalate and octinoxate.[12]

In vitro studies[edit]

Various studies have been done that show the estrogenic and anti-androgenic effects of oxybenzone. A study performed on a line of human breast cancer cells in 2003 validated these claims.[13] This study showed that high concentrations of oxybenzone induced expression of the enzyme luciferase and it was not blocked by the estrogen antagonist. The data showed that there is anti-androgenic and estrogenic activity in vitro.[13]

With exposure to sunlight, oxybenzone has been found to form free radicals through photogeneration, and therefore may be associated with cell damage. This only occurred when it was combined with other ingredients commonly found in sunscreen, like titanium oxide and octyl methoxycinnamate.[14] On its own, oxybenzone was found to be a preferred UVA filter in 1996.[15]

Three out of four studies since 2002 performed in vitro of rats found oxybenzone to have estrogenic potential, as it is a competitive binder of estrogen in the presence of estrogen receptors.[16][17][18][19] These estrogenic effects are additive, meaning oxybenzone is more damaging when combined with other sunscreen ingredients such as benzophenone-1.[20] However, all of these studies assert that the estrogenic potential is ultimately insignificant because in vivo, oxybenzone is broken down into metabolites that show little to no estrogenic activity.

In vivo studies[edit]

An in vivo study done in 2001 demonstrated that oxybenzone has estrogenic activity, meaning the molecule elicits an effect in a manner that mimics natural estrogen.[17] It is difficult to take this result and assume that oxybenzone will produce the same effect in humans because the rats that were used in this particular study were administered an oral dosage of 1500 mg oxybenzone per kg body weight per day which is a phenomenally large dose.[17] The dose used in the 2001 study is significantly larger than the recommended amount of topically applied commercial sunscreen which a study, done by Gonzalez and colleagues in 2002, approximated to be "40 g for an average body area of 2.0 m2."[21] A 2006 study comparing the in vivo and in vitro effects of oxybenzone concluded that the estrogenic activity is abolished in vivo because of metabolism.[18]

Human studies[edit]

The most established risk associated with oxybenzone is its photoallergenic potential. Among common sunscreen chemicals, oxybenzone is most likely to be associated with allergic reactions triggered by sun exposure. In a study of 82 patients with photoallergic contact dermatitis, over one quarter showed photoallergic reactions to oxybenzone.[22]

In a 2008 study of participants ages 6 and up, oxybenzone was detected in 96.8% of urine samples.[23] Humans can absorb anywhere from 0.4% to 8.7% of oxybenzone after one topical application of sunscreen, as measured in urine excretions. This number can increase after multiple applications over the same period of time.[9] Oxybenzone is particularly penetrative because it is the least lipophilic of the three most common UV filters.[10]

The studies that have been done in vitro and in vivo draw attention to the possible effects oxybenzone might have on reproductive hormones produced within the human body. To appraise the effects and risk of topically applied oxybenzone human clinical trials were performed. One such study was performed by several researchers in 2004. Their results showed no significant effect on hormone levels. Although the molecule was absorbed throughout the skin, it was not capable of disrupting the regulation of reproductive hormones in adults.[24]

Most of these studies were only performed on adults. Young children not only have less developed systems of eliminating toxins, but they also have a larger surface area per body weight than adults. This suggests that children might intake larger amounts of compounds when applied topically.[24] Sweden, for example, has advised that sunscreens containing oxybenzone may be unsuitable for children under two years of age.[25] Children this young have not had a chance for the enzymes that degrade the molecule to fully develop and theoretically cannot eliminate the molecule as rapidly as adults putting them as a greater potential risk.[25] For similar reasons, the Food and Drug Administration (FDA) and the International Dermal Institute both recommend to not apply sunscreen to infants because of high surface area to body weight ratios.[26][27] A 2008 study also found a slightly positive correlation between women with high levels of oxybenzone in their system and high birth weight of their sons. There was no correlation with daughter birth weight.[28]

Metabolism[edit]

When applied topically UV filters, such as oxybenzone, are absorbed through the skin, metabolized, and excreted primarily through the urine.[29] The method of biotransformation, the process by which a foreign compound is chemically transformed to form a metabolite, was determined by Okereke and colleagues through oral and dermal administration of oxybenzone to rats. The scientists analyzed blood, urine, feces, and tissue samples and found three metabolites: 2,4-dihydroxybenzophenone (DHB), 2,2-dihydroxy-4-methoxybenzophenone (DHMB) and 2,3,4-trihydroxybenzophenone (THB).[30][31] To form DHB the methoxy functional group undergoes o-dealkylation; to form THB the same ring is hydroxylated.[29] Ring B in oxybenzone is hydroxylated to form DHMB.[29]

A study done in 2004 measured the levels of oxybenzone and its metabolites in urine. After topical application to human volunteers, results revealed that up to 1% of the applied dose was found in the urine.[32] The major metabolite detected was DHB and very small amounts of THB were found.[32] By utilizing the Ames test in Salmonella typhimurium strains, DHB was determinted to be nonmutagenic.[33]

Effects on coral[edit]

New research has shown possible links between benzophenones (along with three other active ingredients) in sunscreens and coral bleaching and die-offs.[34][35][36]

Regulation[edit]

Country Oxybenzone permitted
Australia 10%
Canada 6%
European Union 10%
Japan 5%
Sweden unregulated
United States 6%

Australia[edit]

Revised as of 2007, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS)) Cosmetic Guidelines allow oxybenzone for cosmetic use up to 10%.[37]

Canada[edit]

Revised as of 2012, Health Canada allows oxybenzone for cosmetic use up to 6%.[38]

European Union[edit]

The Scientific Committee on Consumer Products (SCCP) of the European Commission concluded in 2008 that it does not pose a significant risk to consumers, apart from contact allergenic potential.[27] It is allowed in cosmetics up to 10%.

Japan[edit]

Revised as of 2001, the Ministry of Health, Labour, and Welfare notification allows oxybenzone for cosmetic use up to 5%.[39]

Sweden[edit]

The Swedish Research Council has determined that sunscreens with oxybenzone are unsuitable for use in young children, because children under the age of two years have not fully developed the enzymes that are believed break it down. No regulations have come of this study yet.[4]

United States[edit]

Oxybenzone was approved for use in the US by the FDA in the early 1980s. Revised as of April 1, 2013, the FDA allows oxybenzone in cosmetic products up to 6%.[40]

References[edit]

  1. ^ Merck Index, 11th Edition, 6907
  2. ^ a b 131-57-7 Methanone
  3. ^ Fontanals, Núria; Cormack, Peter A.G.; Sherrington, David C.; Marcé, Rosa M.; Borrull, Francesc (2010). "Weak anion-exchange hypercrosslinked sorbent in on-line solid-phase extraction–liquid chromatography coupling to achieve automated determination with an effective clean-up". Journal of Chromatography A 1217 (17): 2855–61. doi:10.1016/j.chroma.2010.02.064. PMID 20303088. 
  4. ^ a b c d e f g h i "Hazardous Substances Data Bank". 2-HYDROXY-4-METHOXYBENZOPHENONE. National Library of Medicine (US), Division of Specialized Information Services. Retrieved 9 March 2014. 
  5. ^ a b c d Burnett, M. E.; Wang, S. Q. (2011). "Current sunscreen controversies: A critical review". Photodermatology, Photoimmunology & Photomedicine 27 (2): 58–67. doi:10.1111/j.1600-0781.2011.00557.x. PMID 21392107.  edit
  6. ^ Castro, G. T.; Blanco, S. E.; Giordano, O. S. (2000). "UV Spectral Properties of Benzophenone. Influence of Solvents and Substituents". Molecules 5 (3): 424. doi:10.3390/50300424. 
  7. ^ Lago, A. F.; Jimenez, P.; Herrero, R.; Dávalos, J. Z.; Abboud, J.-L. M. (2008). "Thermochemistry and Gas-Phase Ion Energetics of 2-Hydroxy-4-methoxy-benzophenone (Oxybenzone)". The Journal of Physical Chemistry A 112 (14): 3201–8. doi:10.1021/jp7111999. PMID 18341312. 
  8. ^ Chrã©Tien, Michelle N.; Heafey, Eve; Scaiano, Juan C. (2010). "Reducing Adverse Effects from UV Sunscreens by Zeolite Encapsulation: Comparison of Oxybenzone in Solution and in Zeolites". Photochemistry and Photobiology 86 (1): 153–61. doi:10.1111/j.1751-1097.2009.00644.x. PMID 19930122. 
  9. ^ a b Gonzalez, H.; Farbrot, A.; Larko, O.; Wennberg, A. M. (2006). "Percutaneous absorption of the sunscreen benzophenone-3 after repeated whole-body applications, with and without ultraviolet irradiation". British Journal of Dermatology 154 (2): 337–40. doi:10.1111/j.1365-2133.2005.07007.x. PMID 16433806.  edit
  10. ^ a b Hanson, K. M.; Gratton, E; Bardeen, C. J. (2006). "Sunscreen enhancement of UV-induced reactive oxygen species in the skin". Free Radical Biology and Medicine 41 (8): 1205–12. doi:10.1016/j.freeradbiomed.2006.06.011. PMID 17015167.  edit
  11. ^ Centers for Disease Control. CDC: Americans Carry Body Burden of Toxic Sunscreen Chemical. Environmental Working Group. EWG, 25 March 2008. Web. 14 March 2014.
  12. ^ "The Trouble With Sunscreen Chemicals". Environmental Working Group, Washington. Retrieved 27 April 2014. 
  13. ^ a b Ma, R; Cotton, B; Lichtensteiger, W; Schlumpf, M (2003). "UV filters with antagonistic action at androgen receptors in the MDA-kb2 cell transcriptional-activation assay". Toxicological Sciences 74 (1): 43–50. doi:10.1093/toxsci/kfg102. PMID 12730620.  edit
  14. ^ Serpone, N; Salinaro, A; Emeline, A. V.; Horikoshi, S; Hidaka, H; Zhao, J (2002). "An in vitro systematic spectroscopic examination of the photostabilities of a random set of commercial sunscreen lotions and their chemical UVB/UVA active agents". Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology 1 (12): 970–81. PMID 12661594.  edit
  15. ^ Allen, J. M.; Gossett, C. J.; Allen, S. K. (1996). "Photochemical Formation of Singlet Molecular Oxygen in Illuminated Aqueous Solutions of Several Commercially Available Sunscreen Active Ingredients". Chemical Research in Toxicology 9 (3): 605. doi:10.1021/tx950197m. PMID 8728505.  edit
  16. ^ Nakagawa, Y; Suzuki, T (2002). "Metabolism of 2-hydroxy-4-methoxybenzophenone in isolated rat hepatocytes and xenoestrogenic effects of its metabolites on MCF-7 human breast cancer cells". Chemico-biological interactions 139 (2): 115–28. PMID 11823001.  edit
  17. ^ a b c Schlumpf, M; Cotton, B; Conscience, M; Haller, V; Steinmann, B; Lichtensteiger, W (2001). "In vitro and in vivo estrogenicity of UV screens". Environmental health perspectives 109 (3): 239–44. PMC 1240241. PMID 11333184.  edit
  18. ^ a b Kunz, P. Y.; Galicia, H. F.; Fent, K (2006). "Comparison of in vitro and in vivo estrogenic activity of UV filters in fish". Toxicological Sciences 90 (2): 349–61. doi:10.1093/toxsci/kfj082. PMID 16403853.  edit
  19. ^ Van Liempd, S. M.; Kool, J; Meerman, J. H.; Irth, H; Vermeulen, N. P. (2007). "Metabolic profiling of endocrine-disrupting compounds by on-line cytochrome p450 bioreaction coupled to on-line receptor affinity screening". Chemical Research in Toxicology 20 (12): 1825–32. doi:10.1021/tx7000724. PMID 17975887.  edit
  20. ^ Heneweer, M; Muusse, M; Van Den Berg, M; Sanderson, J. T. (2005). "Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells". Toxicology and Applied Pharmacology 208 (2): 170–7. doi:10.1016/j.taap.2005.02.006. PMID 16183391.  edit
  21. ^ Gustavsson Gonzalez, H; Farbrot, A; Larkö, O (2002). "Percutaneous absorption of benzophenone-3, a common component of topical sunscreens". Clinical and experimental dermatology 27 (8): 691–4. doi:10.1046/j.1365-2230.2002.01095.x. PMID 12472548.  edit
  22. ^ Rodríguez, E; Valbuena, M. C.; Rey, M; Porras De Quintana, L (2006). "Causal agents of photoallergic contact dermatitis diagnosed in the national institute of dermatology of Colombia". Photodermatology, Photoimmunology & Photomedicine 22 (4): 189–92. doi:10.1111/j.1600-0781.2006.00212.x. PMID 16869867.  edit
  23. ^ Calafat, A. M.; Wong, L. Y.; Ye, X.; Reidy, J. A.; Needham, L. L. (2008). "Concentrations of the Sunscreen Agent Benzophenone-3 in Residents of the United States: National Health and Nutrition Examination Survey 2003–2004". Environmental Health Perspectives 116 (7): 893–7. doi:10.1289/ehp.11269. PMC 2453157. PMID 18629311.  edit
  24. ^ a b Janjua, N. R.; Mogensen, B.; Andersson, A. M.; Petersen, J. H.; Henriksen, M.; Skakkebaek, N. E.; Wulf, H. C. (2004). "Systemic Absorption of the Sunscreens Benzophenone-3, Octyl-Methoxycinnamate, and 3-(4-Methyl-Benzylidene) Camphor After Whole-Body Topical Application and Reproductive Hormone Levels in Humans". Journal of Investigative Dermatology 123 (1): 57–61. doi:10.1111/j.0022-202X.2004.22725.x. PMID 15191542.  edit
  25. ^ a b "Sunscreens with benzophenone-3 unsuitable for children." Swedish Research Council. N.p., 6 November 2006. Web. 14 March 2014.
  26. ^ "Should You Put Sunscreen on Infants? Not Usually." U.S. Food and Drug Administration. U.S. Food and Drug Administration, 10 February 2014.
  27. ^ a b Aguirre, Claudia, "Shedding Light on Sun Safety – Part Two." International Dermal Institute. International Dermal Institute, n.d. Web. 14 March 2014.
  28. ^ Wolff, M. S.; Engel, S. M.; Berkowitz, G. S.; Ye, X.; Silva, M. J.; Zhu, C.; Wetmur, J.; Calafat, A. M. (2008). "Prenatal Phenol and Phthalate Exposures and Birth Outcomes". Environmental Health Perspectives 116 (8): 1092–7. doi:10.1289/ehp.11007. PMC 2516577. PMID 18709157.  edit
  29. ^ a b c Chisvert, A; León-González, Z; Tarazona, I; Salvador, A; Giokas, D (2012). "An overview of the analytical methods for the determination of organic ultraviolet filters in biological fluids and tissues". Analytica Chimica Acta 752: 11–29. doi:10.1016/j.aca.2012.08.051. PMID 23101648.  edit
  30. ^ Okereke, C. S.; Kadry, A. M.; Abdel-Rahman, M. S.; Davis, R. A.; Friedman, M. A. (1993). "Metabolism of benzophenone-3 in rats". Drug metabolism and disposition: the biological fate of chemicals 21 (5): 788–91. PMID 7902237.  edit
  31. ^ Okereke, C. S.; Abdel-Rhaman, M. S.; Friedman, M. A. (1994). "Disposition of benzophenone-3 after dermal administration in male rats". Toxicology letters 73 (2): 113–22. doi:10.1016/0378-4274(94)90101-5. PMID 8048080.  edit
  32. ^ a b Sarveiya, V; Risk, S; Benson, H. A. (2004). "Liquid chromatographic assay for common sunscreen agents: Application to in vivo assessment of skin penetration and systemic absorption in human volunteers". Journal of Chromatography B 803 (2): 225–31. doi:10.1016/j.jchromb.2003.12.022. PMID 15063329.  edit
  33. ^ "Hazardous Substances Data Bank". 2,4-DIHYDROXYBENZOPHENONE. National Library of Medicine (US), Division of Specialized Information Services. Retrieved 19 April 2014.
  34. ^ "Protect Yourself, Protect The Reef! The impacts of sunscreens on our coral reefs". U.S. National Park Service. Retrieved 1 July 2013. 
  35. ^ Than, Ker. "Swimmers' Sunscreen Killing Off Coral". National Geographic News. National Geographic News. Retrieved January 29, 2008. 
  36. ^ http://www.badgerbalm.com/s-35-coral-reef-safe-sunscreen.aspx
  37. ^ "NICNAS COSMETICS GUIDELINES". Australian Government Department of Health. Retrieved 9 March 2014. 
  38. ^ "Guidance Document Sunscreen Monograph". Health Canada. Retrieved 9 March 2014. 
  39. ^ "Standards for Cosmetics". Ministry of Health and Welfare Notification No.331 of 2000. Japanese Government. Retrieved 9 March 2014. 
  40. ^ "SUNSCREEN DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE". Code of Federal Regulations Title 21. FDA. Retrieved 9 March 2014.