Octinoxate (2-Ethylhexyl 4-methoxycinnamate)

Analysis of photokinetics of 2'-ethylhexyl-4-methoxycinnamate in sunscreens

2'-Ethylhexyl-4-Methoxycinnamate (EHMC), also designated as octinoxate, is an oily UV-absorber used in sunscreens for the protection of human skin against solar UV-radiation and represents one of the most employed UVB absorbers for that application. In water-in-oil emulsions EHMC was adjusted at a constant overall concentration, while changing the EHMC concentration in the oil droplets by adding a non-absorbing oil. In that way the EHMC concentration could be varied at constant optical thickness. Here we show that the kinetics of the photoreaction follows a second-order rate law, in line with the UV-induced [2 + 2]-cycloaddition reaction mechanism known for this UV absorber. The second-order rate constant decreased with higher overall EHMC concentration. This can be explained by the fact, that at higher overall concentration of the UV absorber not every EHMC molecule will absorb a photon due to the increased optical density, so that on average less photons are absorbed per molecule. On the other hand, the rate constant increases with decreasing polarity of the surrounding oil. Since the molar fraction of the trans-isomer of EHMC is augmented at lower polarity, more photons are absorbed in this case, as the strength of the absorption band of the trans-isomer is significantly higher than that of the cis-isomer. In conclusion, our experiments show that a high polarity of the oil phase and a high concentration of EHMC are advantageous for the photostability of this compound.

Biodegradation of 2-ethylhexyl-4-methoxycinnamate in river sediments and its impact on microbial communities

Numerous studies have evaluated the toxicity and endocrine disrupting properties of organic UV filters for aquatic organisms, but little is known about their biodegradation in river sediments and their impact on microorganisms. We have set up the sterile and microbiological systems in the laboratory, adding 2-ethylhexyl-4-methoxycinnamate (EHMC), one of organic UV filters included in the list of high yield chemicals, at concentrations of 2, 20 and 200 μg/L, and characterized the microbial community composition and diversity in sediments. Monitoring of EHMC degradation within 30 days revealed that the half-life in the microbial system (3.49 days) was much shorter than that in the sterile system (7.55 days). Two potential degradation products, 4-mercaptobenzoic acid and 3-methoxyphenol were identified in the microbial system. Furthermore, high-throughput 16s and 18s rRNA gene sequencing showed that Proteobacteria dominated the sediment bacterial assemblages followed by Chloroflexi, Acidobacteria, Bacteroidetes and Nitrospirae; Eukaryota_uncultured fungus dominated the sediment fungal assemblages. Correlation analysis demonstrated that two bacterium genera (Anaerolineaceae_uncultured and Burkholderiaceae_uncultured) were significantly correlated with the biodegradation of EHMC. These results illustrate the biodegradability of EHMC in river sediments and its potential impact on microbial communities, which can provide useful information for eliminating the pollution of organic UV filters in natural river systems and assessing their potential ecological risks.

Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA).
Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions.
Design, setting, and participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019.
Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant.
Main outcomes and measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21.
Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants.
Conclusions and relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen.
Trial registration: ClinicalTrials.gov Identifier: NCT03582215.

Effects of 2-ethylhexyl-4-methoxycinnamate (EHMC) on thyroid hormones and genes associated with thyroid, neurotoxic, and nephrotoxic responses in adult and larval zebrafish (Danio rerio)

One of the most widely used UV filters, 2-ethylhexyl-4-methoxycinnamate (EHMC), has been widely detected in the environment. While its endocrine disruption potential has often been reported, toxicological information on EHMC is limited. This study was conducted to determine the thyroid, neurological and renal toxicity potentials of EHMC in adult male and embryo-larval zebrafish (Danio rerio). Following 21 d of exposure, plasma T3 concentration decreased in a concentration-dependent manner in adult zebrafish. Several genes related to thyroid hormone regulation were also downregulated in the brain, thyroid, and liver of the adult fish. In addition, upregulation of syn2a in the brain and downregulation of podocin and wt1a in the kidney were observed following the exposure in adult fish. In zebrafish larvae, following 120 h exposure to EHMC, whole-body T3 and T4 contents decreased, and thyroid hormone-related genes were downregulated. However, several genes showed different patterns of transcription in the larvae; for example, mbp and etv1 genes were downregulated and podocin was upregulated. Unlike adult fish, the larval fish showed significant genetic changes related to neurotoxicity. The hypothyroidism induced in the larval fish by the exposure might be potentially associated with the neurotoxic potential of EHMC. The implications of the observed hormonal and transcriptional-level changes in zebrafish at different life stages following long-term exposure warrant further investigation.

Sunscreens: are they beneficial for health? An overview of endocrine disrupting properties of UV-filters

Today, topical application of sunscreens, containing ultraviolet-filters (UV-filters), is preferred protection against adverse effects of ultraviolet radiation. Evidently, use of sunscreens is effective in prevention of sunburns in various models. However, evidence for their protective effects against melanoma skin cancer is less conclusive. Three important observations prompted us to review the animal data and human studies on possible side effects of selected chemical UV-filters in cosmetics. (1) the utilization of sunscreens with UV-filters is increasing worldwide; (2) the incidence of the malignant disorder for which sunscreens should protect, malignant melanoma, is rapidly increasing and (3) an increasing number of experimental studies indicating that several UV-filters might have endocrine disruptive effects. The selected UV-filters we review in this article are benzophenone-3 (BP-3), 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), Homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate (OD-PABA) and 4-aminobenzoic acid (PABA). The potential adverse effects induced by UV-filters in experimental animals include reproductive/developmental toxicity and disturbance of hypothalamic-pituitary-thyroid axis (HPT). Few human studies have investigated potential side effects of UV-filters, although human exposure is high as UV-filters in sunscreens are rapidly absorbed from the skin. One of the UV-filters, BP-3, has been found in 96% of urine samples in the US and several UV-filters in 85% of Swiss breast milk samples. It seems pertinent to evaluate whether exposure to UV-filters contribute to possible adverse effects on the developing organs of foetuses and children.