Chemical characterization of menstrual and intimate care products: An extractables & leachables investigation

Background: Menstrual and intimate care products (MICPs) such as tampons, menstrual pads, menstrual cups, and adult novelties are widely used worldwide for women’s menstrual comfort or pleasure, respectively. However, growing consumer concerns regarding the presence of hazardous chemicals in these products have been raised. Methods: The aim of this study was to obtain an accurate overview of potential hazardous chemicals (organic and inorganic) that are present in MICPs and to determine the quantities that might leach under typical in-use conditions. Hereto, we developed a workflow analogous to the biological evaluation of medical devices (ISO-10993), encompassing three steps: (1) Conducting extraction experiments under exaggerated conditions and developing analytical methods to identify all chemical constituents (extractables); (2) Prioritizing the extracted chemicals based on available regulatory hazard information, eventually supplemented with in silico toxicological data; (3) Performing migration studies using simulants of vaginal and menstrual fluids, followed by targeted quantification of the prioritized leachable chemicals using newly developed analytical methodologies. The established strategy was applied to 64 MICPs, including absorbent menstrual products (i.e. tampons (n = 9) and menstrual pads (n = 6)), adult novelties (n = 15), menstrual cups (n = 15), Kegel-exercise devices (n = 14) and menstrual sea sponges (n = 5), all products originating from EU, US and China. Results: (1) Extractables assessment revealed the presence of 55 unique chemicals, including phthalates, siloxanes, volatile organic compounds (VOCs), fragrances, and plastic additives. (2) A hazard-based prioritization step highlighted phthalates (DEHP, DiNP, DBP), styrene, and ethylbenzene as the top chemicals for further investigation. (3) The leaching simulation experiments revealed that 65 %, i.e. 36 of the 55 chemicals identified in the extractables assessment were not detected in the leachables assessment. The 19 leachable chemicals identified comprised 9 fragrances, 5 phthalates, 2 plastic additives and 3 VOCs. Their maximum levels quantified were 28.22 µg/g (heliotropine), 100 ppb (DEHP), 18 ppm (triethyl citrate), and 0.24 ppm (2-ethyl-1-hexanol), respectively. In addition to the analysis of organic chemicals, examination of metals and metalloids revealed that menstrual sea sponges had the highest levels of metals and metalloids leaching among all tested menstrual and intimate care product categories, with Nickel, Cadmium, Antimony, and Mercury reaching levels of 1850, 1.0, 0.3, and 0.6 ppm, respectively. Conclusion: This study provides new insights into the chemical composition of MICPs. Furthermore, it demonstrates that the majority of hazardous chemicals present in the studied MICPs are not detected under realistic use conditions; however exposure to phthalates, fragrances and other chemical constituents remains possible

Evaluation of a screening system for obesogenic compounds : screening of endocrine disrupting compounds and evaluation of the PPAR dependency of the effect

Recently the environmental obesogen hypothesis has been formulated, proposing a role for endocrine disrupting compounds (EDCs) in the development of obesity. To evaluate this hypothesis, a screening system for obesogenic compounds is urgently needed. In this study, we suggest a standardised protocol for obesogen screening based on the 3T3-L1 cell line, a well-characterised adipogenesis model, and direct fluorescent measurement using Nile red lipid staining technique. In a first phase, we characterised the assay using the acknowledged obesogens rosiglitazone and tributyltin. Based on the obtained dose-response curves for these model compounds, a lipid accumulation threshold value was calculated to ensure the biological relevance and reliability of statistically significant effects. This threshold based method was combined with the well described strictly standardized mean difference (SSMD) method for classification of non-, weak- or strong obesogenic compounds. In the next step, a range of EDCs, used in personal and household care products (parabens, musks, phthalates and alkylphenol compounds), were tested to further evaluate the obesogenicity screening assay for its discriminative power and sensitivity. Additionally, the peroxisome proliferator activated receptor γ (PPARγ) dependency of the positive compounds was evaluated using PPARγ activation and antagonist experiments. Our results showed the adipogenic potential of all tested parabens, several musks and phthalate compounds and bisphenol A (BPA). PPARγ activation was associated with adipogenesis for parabens, phthalates and BPA, however not required for obesogenic effects induced by Tonalide, indicating the role of other obesogenic mechanisms for this compound

Disulfide Cyclized Tripeptide Analogues of Angiotensin IV as Potent and Selective Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)

The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.</p

Titanium dioxide levels in food and other ingested consumer products: a systematic review

Highlights• Titanium dioxide is present in a variety of food, medicine and personal care products.• It is often found in confectionery and fine bakery products.• A total of 674 individual product concentrations were collected.• The concentrations range from &lt;1 to 51,000 mg/kg.• The presence of natural titanium is negligible in most foods.Graphical abstract is available on https://www.sciencedirect.com/science/article/pii/S2772753X2500034

Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor

Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C-terminal of angiotensin IV with an o-substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a -turn in the C-terminal of its bioactive conformation.Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor.</p

Metal ion modulation of cystinyl aminopeptidase

Cystinyl aminopeptidase has one Zn(2+)-binding motif and is a member of the M1 aminopeptidase family. Ion modulation of its catalytic activity was studied in membranes of CHO-K1 cells (Chinese-hamster ovary K1 cells) using L-leucine-p-nitroanilide as substrate. The planar bidentate chelators 1,10-phenanthroline and 2,2′-bipyridine inhibited the activity in a concentration-dependent manner with Hill slopes of 3.32±1.78 and 2.10±0.26 respectively. The acetic acid-containing chelators EDTA, EGTA and DTPA (diethylenetriamine-N,N,N′,N″,N″-penta-acetic acid) weakly affected the activity, but they increased the potency of the planar chelators up to a limit, at which Hill slopes became close to unity. Moreover, competition between 1,10-phenanthroline and the substrate only took place in the presence of EDTA. These findings are compatible with a model in which the bidentate chelators inhibit enzyme activity by decreasing the free Zn(2+) concentration. By removing a modulatory ion from an allosteric site at the enzyme, the acetic acid-containing chelators facilitate the direct interaction between the bidentate chelators and the catalytic Zn(2+). The inhibitory effect of EDTA plus 1,10-phenanthroline could be completely reversed by Zn(2+). Ca(2+) and Mg(2+) increased the potency of Zn(2+) for this process. This is expected if they interact with the modulatory site to decrease the sensitivity of the enzyme towards 1,10-phenanthroline. Conversely, the bidendate chelators increased the high-affinity [(125)I]angiotensin IV binding to the membranes and this was potentiated by the acetic acid-containing chelators. These findings support the concept that high-affinity [(125)I]angiotensin IV binding, previously referred to as ‘AT(4) receptor binding’, only occurs for the cystinyl aminopeptidase apoenzyme