Cécile Marie

PhD ; Ronan Garlantézec

PhD ; Rémi Béranger

Brest Anne-Sophie Ficheux

Cecile Marie
email: cecile.marie@ars.sante.fr

Julie Bercherie

Jonathan Bernard

Clermont-Ferrand Nathalie Boisseau

Aurore Camier

Montpellier Corinne Chanal

Bérénice Doray

Anne Evrard

Ronan Garlantézec

Saint- Anne Laurent-Vannier

Maurice ; Marion

Clermont- Cécile Marie

Montpellier Françoise Molénat

Fabienne Pelé

Professor Valérie Sautou

Dr Mathieu Wasiak

Dr Mireille Jouannet

Use of Cosmetic Products in Pregnant and Breastfeeding Women and Young Children: Guidelines for Interventions during the Perinatal Period from the French National College of Midwives (5)

Keywords: cosmetic products, guidelines for clinical practice, pregnant women, young children, maternal exposures

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

A cosmetic product is defined by the European Union (EU) as any substance or mixture intended to be placed in contact with the external parts of the human body (epidermis, hair systems, nails, lips and external genital organs) or with the teeth and the mucosa membranes of the oral cavity with a view, exclusively or mainly, to cleaning them, perfuming them, changing their appearance, protecting them, keeping them in good condition or correcting body odours. [START_REF]Règlement (CE) n°1223/2009 du Parlement européen et du Conseil du 30 novembre 2009 relatif aux produits cosmétiques[END_REF] The term cosmetics groups together a broad range of types of products: for hygiene and toiletry (shampoos, shower gels, soaps, deodorants, toothpaste, etc.), hair care (conditioners, styling products, colorants, etc.), face and body care (moisturizing, firming, anti-aging, massage products, etc.), makeup (foundation, mascaras, lipsticks, etc.), fragrance (perfumes, eau de toilette, etc.), shaving and depilation products, sun care, and baby products (diapers, wipes, etc.). A cosmetic product is considered to be the result of a combination of several ingredients; it is therefore a mixture. A cosmetic ingredient is defined as any substance, natural or synthetic, used in the formulation of a cosmetic product.

The cosmetic products available on the European market are subject to European (EC) regulation 1223/2009, commonly known as the cosmetics regulation. [START_REF]Règlement (CE) n°1223/2009 du Parlement européen et du Conseil du 30 novembre 2009 relatif aux produits cosmétiques[END_REF] It mandates that cosmetic products available for sale must be safe for human health in normal or reasonably predictable conditions of use. In other words, no known risk for the health of consumers is tolerated. For this purpose, the manufacturer must evaluate the safety of all of the ingredients contained in the product and must conduct an evaluation of the safety of the finished product before it is marketed. [START_REF]Règlement (CE) n°1223/2009 du Parlement européen et du Conseil du 30 novembre 2009 relatif aux produits cosmétiques[END_REF][START_REF]Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation -10th Revision[END_REF] A specific evaluation of the safety of products intended for children younger than 3 years is also required. Thus, some compounds authorized in cosmetic products intended for the general population can be banned or limited in terms of their concentrations and/or type of product. [START_REF]Règlement (CE) n°1223/2009 du Parlement européen et du Conseil du 30 novembre 2009 relatif aux produits cosmétiques[END_REF] For example, in France, as part of an expert assessment, the Agence Nationale de Sécurité du Médicament (national agency for drug and health safety, ANSM) issued guidelines in 2018 that limit the use of phenoxyethanol in cosmetic products intended for the buttocks of small children. 3 ACCEPTED MANUSCRIPT / CLEAN COPY Since 1999, it has been mandatory to list the complete composition of all cosmetic products on their packaging [INCI (International Classification of Cosmetic Ingredients) list]:

the ingredients present at concentrations exceeding 1% must be classified in decreasing order of concentration; those present at concentrations less than 1% can be mentioned in any order. Nonetheless, for perfumes, regardless of their composition, only the generic term perfume or fragrance must be mentioned; some components used in perfumes and scented products (shower gels, body creams, etc.) can thus not be included on the ingredient list. [START_REF]Règlement (CE) n°1223/2009 du Parlement européen et du Conseil du 30 novembre 2009 relatif aux produits cosmétiques[END_REF] Cosmetics are habitually used more often by women than men. Pregnancy is a period when women are likely to use cosmetic products because changes in their skin (dryness, stretch marks, etc.) can induce them to increase their use of, for example, moisturizing products.

Cosmetics can then be perceived as beneficial products providing bodily well-being.

Nonetheless, this use is not risk-free for the health of either the pregnant women or the unborn child. Cosmetic products contain various compounds, some of which have possibly toxic effects. For example, some substances present in cosmetics can potentially cause endocrine disruption. The presumed effects of endocrine disruptors are varied, including metabolic disorders (obesity and diabetes), some fertility disorders, and an increased risk of some cancers (breast, prostate, and testes). For pregnant women, there also exists an increased risk of unfavorable pregnancy outcomes (eg, small-for-gestational-age neonate, preterm birth, and congenital malformations) or impairments in children's neurodevelopment (such as cognition, behavior, and autism spectrum disorder). [START_REF] Kahn | Endocrine-disrupting chemicals: implications for human health[END_REF] Mechanisms other than endocrine disruption are nonetheless possible for some chemical substances, including direct toxicity or epigenetic mechanisms that can induce long-lasting effects throughout life and even be transmitted to the generations to come. [START_REF] Boekelheide | Predicting later-life outcomes of earlylife exposures[END_REF] Pregnancy is also a period of vulnerability in relation to these substances, since they may affect the development and growth of the embryo and then the fetus because of its immature metabolism. [START_REF] Renzo | International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals[END_REF] Moreover, cutaneous problems (stretch marks, dryness, etc.) can increase skin permeability and thus internal exposure. The skin of young children, especially newborns and in often irritated zones, such as the buttocks, is more permeable to substances than that of adults. [START_REF] Renesme | Recommendation for hygiene and topical in neonatology from the French Neonatal Society[END_REF] The objective of this article is to present a synthesis of the knowledge available about cosmetic use by women either pregnant or breastfeeding and for young children and about the risks associated with it. Based on these elements, we propose here clinical practice guidelines for health care professionals working with pregnant women and parents.

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METHODS

For this systematic review of the scientific literature published in English and in French between 2009 and 2020, ASF and CM searched the MEDLINE database looking for the following themes: use of cosmetic products by women either pregnant or breastfeeding and for young children; exposure to compounds present in cosmetic products and its health effects; and perception of risks by women and health care professionals. The gray literature (publications of guidelines and reports by national bodies, dissertations, and websites) was also analyzed.

RESULTS

Use of Cosmetic Products by Women Either Pregnant or Breastfeeding or for Young

Children

Only limited data are available about the use of cosmetic products by pregnant or breastfeeding women and for children younger than 3 yearsboth in France and throughout the world. The results described for product use below are limited to France.

Pregnant Women

In France, the largest national consumer survey, performed via Internet in 2013 among 251 pregnant women sampled by the quota method, collected data about the use and the frequency of use of 141 types of cosmetics. [START_REF] Ficheux | Consumption of cosmetic products by the French population. First part: frequency data[END_REF] The mean daily number of cosmetic products used was higher for pregnant (n=18 products) than nonpregnant (n=16) women (n=2713). The proportion of users was similar for pregnant and nonpregnant women for most cosmetic products. Hair coloring was nonetheless more frequent among nonpregnant women (46% vs 38% among pregnant women). Inversely, products against stretch marks (6% vs 50%) and for personal hygiene (48% vs 63%) were used more frequently by pregnant women. The frequency of use of these various products remained unchanged during pregnancy, except for a few; during pregnancy, frequency of use increased for shampoos and stretch mark products and diminished for hairspray, face cleansers and makeup removers (micellar cleansing water and cleansing milk), and some makeup products (eyeliner and lip liner) (Table 1). Pregnant women also used ACCEPTED MANUSCRIPT / CLEAN COPY products intended for children more often (shampoos, toothpaste, shower gel, and eau de toilette; 20% vs 10% in nonpregnant women).

A cross-sectional study conducted in 2015 among 128 women (68 pregnant and 60 not) in the Loire and the Haute-Loire districts (France) [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF] collected information about their habits for the use of 28 types of cosmetic products during and outside of pregnancy (regular use when not pregnant, change of use during pregnancy, and criteria for choice to use them). Outside of pregnancy, the products most often used regularly were shampoo, shower gel, deodorant, and perfume (more than 90% of nonpregnant women used them regularly); the products used least often were self-tanning products (1%), lip liner (9%), dermatologic soap (17.5%), and night cream for the face (19%). Globally, the results showed that few women intended to or did modify their cosmetic use during pregnancy; nonetheless more women reported the use of nail polish, nail polish remover (P < .05), and hair dye (P< 0.1) before than during pregnancy. Use of nail polish was stopped during pregnancy by 10% of pregnant women and use of hair coloring by 7%. Moreover, 10% of the pregnant women reported reducing (without totally stopping) their use of perfume. Inversely, moisturizing body cream was the only product whose use rose because of pregnancy (both the proportion of users and frequency of use). [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF] In another cross-sectional study of 300 women (153 pregnant and 147 during the postpartum period) in the district of Vienne (France) in 2015-2016, 13% of women reported limiting their use of cosmetics during pregnancy (generally without distinguishing between types of cosmetics). [START_REF] Rouillon | Endocrine Disruptors and Pregnancy: Knowledge, Attitudes and Prevention Behaviors of French Women[END_REF] A 2017 study at the Bordeaux University Hospital Center (France) found a higher proportion of women who had reduced their cosmetic use during pregnancy: hair coloring (73% of women), nail polish (60%), perfume and/or deodorant (40%). [START_REF] Teysseire | Perception of Environmental Risks and Behavioral Changes during Pregnancy: A Cross-Sectional ACCEPTED MANUSCRIPT / CLEAN COPY Study of French Postpartum Women[END_REF] Despite the differences in percentages, the types of products frequently stopped or reduced during pregnancy (hair coloring, nail polish, perfume, deodorant) are consistent with the results in the study by Marie et al. (2016). [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF] Moreover, the differences in results can be explained by differences in methodology (number of women included, periods of inclusion, etc.) or by different analytic criteria. Including postpartum women (after normal birth) involves risks of memory and reporting bias. Finally, the impact of local prevention policies cannot be ruled out, especially in the study by Teysseire et al. (2019), in which nearly half the women reported receiving information about environmental risks from their physicians. [START_REF] Teysseire | Perception of Environmental Risks and Behavioral Changes during Pregnancy: A Cross-Sectional ACCEPTED MANUSCRIPT / CLEAN COPY Study of French Postpartum Women[END_REF] A recent French study considered the use of essential oils; among the 128 included women either pregnant or postpartum, 18% reported using essential oils during pregnancy. [START_REF] Cabut | Intended and actual use of selfmedication and alternative products during pregnancy by French women[END_REF]

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Children Younger than 3 Years

A national consumer survey via Internet in 2013 focused on the types of cosmetics used and their frequency of use for 395 children younger than 3 years. [START_REF] Ficheux | Consumption of cosmetic products by the French population second part: Amount data[END_REF] Parents used an average of 6 cosmetic products daily for their child. The products most widely used were shampoo (87% of users), shower gel (77%), wipes (77%), toothpaste (62%), eau de toilette (47%), and products intended for the buttocks, such as oleo-limestone liniment (33%) or cleansing water (29%).

Wipes, very widely used by parents despite controversies related to their composition, were used to clean different parts of babies' bodies, especially the buttocks (64% of users), face (48%), and hands (25%). Based on the data about product quantities used in this study, the authors estimated that exposure to cosmetic products and therefore to their ingredients was much greater among children younger than 3 years than adults (especially for toothpaste, moisturizing products, and shower gel). 14

Consequences Associated with the Use of Cosmetic Products

Exposure to Chemical Substances

Composition of a Cosmetic Product

Cosmetic formulas are most often composed of an aqueous phase and a fatty phase homogenized by substances with emulsifying properties. A cosmetic product thus has a variable number of ingredients, each with a specific function. The ingredients that create the product's texture (thickeners and gelling agents) and serve as a support for the active ingredients often account for most of its composition (water is generally the major component at 40 to 85% of the product). The ingredients that make the product effective (hydration, cell regeneration, soothing, photo-protection, anti-aging, etc.), on the other hand, generally account for less than 3% of the product. Other ingredients (preservatives, fixatives, colorants, etc.) may also be present to improve the product's effectiveness and duration of effect. Cosmetic products thus contain numerous chemical substances: phthalates, phenols, parabens, antibacterials, organic solvents, formaldehyde, heavy metals, and more. [START_REF] Bocca | Toxic metals contained in cosmetics: a status report[END_REF][START_REF] Juhász | A review of selected chemical additives in cosmetic products[END_REF][START_REF] Koniecki | Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure[END_REF][START_REF] Witorsch | Personal care products and endocrine disruption: A critical review of the literature[END_REF][START_REF] Debacker | Conservation des produits cosmétiques : évolutions, risques associés et stratégies d'optimisation[END_REF]

Exposure Routes

The ingredients can penetrate the organism through different exposure routes. Most cosmetic products are directly applied to the skin, and their components can cross the cutaneous barrier to reach the systemic circulation. Exposure can also take place by inhalation (for cosmetics in ACCEPTED MANUSCRIPT / CLEAN COPY the form of aerosols or sprays, such as hairspray, perfumes, some deodorants, or during the application of nail polish, for example), and, more rarely, by ingestion (for toothpaste or lipstick). [START_REF] Ficheux | Consumption of cosmetic products by the French population second part: Amount data[END_REF][START_REF] Chevillotte | Exposure method development for risk assessment to cosmetic products using a standard composition[END_REF] During application to the skin, it is necessary to distinguish rinsable products (soap, shampoo, shower gel, etc.) and those that are not immediately rinsed off (perfume, deodorant, moisturizing cream, wipes for baby, etc.). The ingredients in the nonrinsable products remain in contact with the organism and thus expose their users still more. [START_REF] Renesme | Recommendation for hygiene and topical in neonatology from the French Neonatal Society[END_REF] Data about Exposure to the Chemical Substances Contained in Cosmetics Numerous studies, in particular in the United States, have shown that among adults the use of cosmetic products is associated with a higher level of exposure to some substances:

-To phenols, such as the parabens, [START_REF] Braun | Personal care product use and urinary phthalate metabolite and paraben concentrations during ACCEPTED MANUSCRIPT / CLEAN COPY pregnancy among women from a fertility clinic[END_REF][START_REF] Janjua | Systemic uptake of diethyl phthalate, dibutyl phthalate, and butyl paraben following whole-body topical application and reproductive and thyroid hormone levels in humans[END_REF][START_REF] Larsson | Exposure determinants of phthalates, parabens, bisphenol A and triclosan in Swedish mothers and their children[END_REF] and to some ketones, such as benzophenone-3 [START_REF] Mínguez-Alarcón | Urinary concentrations of benzophenone-3 and reproductive outcomes among women undergoing infertility treatment with assisted reproductive technologies[END_REF] -To phthalates, in particular, diethyl phthalate (DEP) and dibutyl phthalate (DiBP) [START_REF] Koniecki | Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure[END_REF][START_REF] Braun | Personal care product use and urinary phthalate metabolite and paraben concentrations during ACCEPTED MANUSCRIPT / CLEAN COPY pregnancy among women from a fertility clinic[END_REF][START_REF] Janjua | Systemic uptake of diethyl phthalate, dibutyl phthalate, and butyl paraben following whole-body topical application and reproductive and thyroid hormone levels in humans[END_REF][START_REF] Buckley | Consumer product exposures associated with urinary phthalate levels in pregnant women[END_REF][START_REF] Martina | Lifestyle behaviors associated with exposures to endocrine disruptors[END_REF][START_REF] Parlett | Women's exposure to phthalates in relation to use of personal care products[END_REF][START_REF] Philippat | Exposure to Phthalates and Phenols during Pregnancy and Offspring Size at Birth[END_REF] and bis(2-ethylhexyl) phthalate (DEHP), [START_REF] Braun | Personal care product use and urinary phthalate metabolite and paraben concentrations during ACCEPTED MANUSCRIPT / CLEAN COPY pregnancy among women from a fertility clinic[END_REF][START_REF] Janjua | Systemic uptake of diethyl phthalate, dibutyl phthalate, and butyl paraben following whole-body topical application and reproductive and thyroid hormone levels in humans[END_REF][START_REF] Buckley | Consumer product exposures associated with urinary phthalate levels in pregnant women[END_REF][START_REF] Martina | Lifestyle behaviors associated with exposures to endocrine disruptors[END_REF][START_REF] Parlett | Women's exposure to phthalates in relation to use of personal care products[END_REF][START_REF] Philippat | Exposure to Phthalates and Phenols during Pregnancy and Offspring Size at Birth[END_REF][START_REF] Romero-Franco | Personal care product use and urinary levels of phthalate metabolites in Mexican women[END_REF][START_REF] Koniecki | Phthalates in cosmetic and personal care products: Concentrations and possible dermal exposure[END_REF] -To triphenyl phosphate (TPHP). [START_REF] Mendelsohn | Nail polish as a source of exposure to triphenyl phosphate[END_REF] Studies in France are rarer. An analysis by Santé publique France (the French public health agency) among 4145 women from the ELFE cohort (continental France mother-child cohort) found a total urinary concentration of DEHP metabolites 27% (95% CI, 1.8%-58.0%) higher among women using more than 5 cosmetic products a day compared to women using 2 to 3 a day. [START_REF]Exposition Des Femmes Enceintes Françaises Aux Polluants de l'environnement : Santé Publique France Publie Les Premiers Résultats de l'étude -Tome 1 : Les Polluants Organiques[END_REF] Nisse et al. (2017) found a urinary concentration of phenoxyacetic acid (a metabolite of phenoxyethanol used as a preservative in cosmetics) higher among women than men. [START_REF] Nisse | Caractérisation de l'exposition aux éthers de glycol d'un échantillon de population générale du Nord-Pas-de-Calais par biométrologie urinaire[END_REF] In this study of 120 adults in the general population of Nord-Pas-de-Calais, the use of cosmetics (in particular, body and face care, hand or foot creams) was the only identifiable factor associated with higher levels. Finally, Garlantézec et al. (2012), in a random sample of 451 women in the French PELAGIE cohort (Bretagne) found a higher urinary concentration of phenoxyacetic acid among hairdressers and beauticians than for the other occupations considered (geometric means [GM]: 1.17 mg/L urine for the group of hairdressers and beauticians vs 0.41 for the others, P=.03). [START_REF] Garlantézec | Urinary biomarkers of exposure to glycol ethers and chlorinated solvents during pregnancy: determinants of exposure and comparison with indirect methods of exposure assessment[END_REF] More recently, the ESTEBAN study (Etude de Santé sur l'Environnement, la Biosurveillance, l'Activité physique et la Nutrition, that is, of health related to the environment, biomonitoring, physical activity, and nutrition) examined the urinary concentrations of different pollutants in up to 500 children and 900 adults in 2014-2016 ACCEPTED MANUSCRIPT / CLEAN COPY (the number of participants varied for the different chemical families). In adults, the study reported quantifiable levels in 99.8% of subjects for phenoxyacetic acid (GM: 0.254 mg/L urine), with a higher concentration in participants who reported using deodorants (+55.7%) or cosmetics (+147 %). [START_REF] Spf | Imprégnation de la population française par les éthers de glycol[END_REF] For parabens, the level of urinary detection ranged from 0% (pentyl-and heptyl-parabens) to 93.3% (methyl-parabens; GM: 8.15 µg/L), with a 97% augmentation in the level of methyl-parabens in participants reporting using creams and other products for the body and a 207% increase in those reporting use of cosmetic products. [START_REF] Spf | Imprégnation de la population française par les parabènes[END_REF] For short-chain phthalate metabolites, principally related to cosmetic product use, the urinary detection rate ranged from 93.8% (mono-methyl phthalate [MMP], GM: 2.4 µg/L urine) to 100% (monoisobutyl phthalate

[MiBP] and monoethyl phthalate [MEP], GM: 28.5 and 52.0 µg/L urine, respectively). [START_REF] Spf | Imprégnation de la population française par les phtalates. Programme national de biosurveillance, Esteban 2014-2016[END_REF] We note that in the ESTEBAN study the term cosmetics included makeup products and nail polish and its remover, but not hygiene products, deodorant, hair coloring, or creams and lotions for the body.

Although some surveys have tried to estimate the impact of cosmetic use on exposure levels in children with probabilistic approaches, [START_REF] Ficheux | Probabilistic assessment of exposure to cosmetic products by French children aged 0-3 years[END_REF] we currently lack studies based on real measurements. In a study of a sample of children aged 6 years in the PELAGIE cohort, the presence of phenoxyacetic acid was found in all of the (median concentration: 0.141 mg/L). [START_REF] Garlantézec | Exposure to glycol ethers among 6year-old children in France[END_REF] In the ESTEBAN study, the detection frequencies were similar in children and adults for phthalates, glycol ethers, and parabens. Urinary concentrations of short-chain phthalate metabolites and DEHP were higher in children for whom cosmetic product use was reported (+32.8% and +32.9%, respectively). [START_REF] Spf | Imprégnation de la population française par les phtalates. Programme national de biosurveillance, Esteban 2014-2016[END_REF] Cosmetics also contain numerous nanoparticles likely to cause exposure in users, including to some possibly toxic metallic particles. [START_REF] Borowska | Metals in cosmetics: implications for human health[END_REF] Nonetheless, the real impact of exposure to such levels of contamination remains unknown.

Effect on the Health of Pregnant Women and their Unborn Children

Irritations and Allergies

Numerous substances (preservatives, surfactants, UV filters, fragrances, etc.) contained in cosmetic products are identified as allergens and irritants. Some natural nut oils (such as almond oil, sesame oil, etc.) and essential oils also present allergic risks. [START_REF] Agne | Sesame seed allergy in children[END_REF][START_REF]Sprays et diffuseurs à base d'huiles essentielles à usage domestique[END_REF] In 2012, the European Scientific Committee for Consumer Safety (CSSC) listed 82 substances associated with ACCEPTED MANUSCRIPT / CLEAN COPY fragrances as able to induce allergies. [START_REF] Sccs | Opinion on fragrance allergens in cosmetic products[END_REF] Nonetheless, European regulations currently recognize only 26 substances (Citronellol, Geraniol, Coumarin, Limonene, etc.) as allergens that must be indicated on product packaging. [START_REF]Règlement (CE) n°1223/2009 du Parlement européen et du Conseil du 30 novembre 2009 relatif aux produits cosmétiques[END_REF]

Effects on Reproduction and Development

While cosmetic exposure is very frequent in household settings, it is also frequent for women in some occupational settings, and probably at higher levels. Several studies have examined the association between occupational exposure to these products and reproductive and developmental abnormalities. A meta-analysis reported an increase in the risk of stillbirths, of births with a time to conception greater than 12 months, and of fetal growth restriction among women working as hairdressers or beauticians. [START_REF] Henrotin | Reproductive disorders in hairdressers and cosmetologists: a meta-analytical approach[END_REF] However, the studies included covered a halfcentury period (1960-2010): the chemical composition of cosmetic products undoubtedly varied not only over time but also by country. Moreover, most of the studies considered did not take into account postural (such as prolonged standing positions) or psychosocial constraints potentially important for the study of some reproductive and developmental abnormalities (for example, miscarriages and preterm births).

The literature rarely directly associates the use of cosmetic products during pregnancy or in young children with developmental disorders of the fetus and/or child. On the other hand, some studies and reviews in the international literature show an association between exposure to different substances present in cosmetics (including phthalates, parabens, phenoxyethanol, triclosan, and benzophenone) and the risks of preterm birth, fetal growth restriction, congenital malformations, and neurodevelopmental impairment. [START_REF] Renzo | International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals[END_REF][START_REF] Ejaredar | Phthalate exposure and childrens neurodevelopment: A systematic review[END_REF][START_REF] Ghazipura | Exposure to benzophenone-3 and reproductive toxicity: A systematic review of human and animal studies[END_REF][START_REF] Marie | Obstetrical outcomes and biomarkers to assess exposure to phthalates: A review[END_REF][START_REF] Jiang | Prenatal exposure to benzophenones, parabens and triclosan and neurocognitive development at 2 years[END_REF][START_REF] Zhong | Association of prenatal exposure to phenols and parabens with birth size: A systematic review and meta-analysis[END_REF] Some questionnaire-based studies have suggested an association with the risk of congenital malformation in children. In a case-control study in Picardie (France) between 2011 and 2014 (219 newborns, including 57 cases born with hypospadias), the use of hairspray and hair colorants during pregnancy was associated with a higher risk of hypospadias (odds ratio

[OR], 1.8; 95% CI, 1.0-3.6), after adjustment for potential confounding factors. [START_REF] Haraux | Maternal Exposure to Domestic Hair Cosmetics and Occupational Endocrine Disruptors Is Associated with a Higher Risk of ACCEPTED MANUSCRIPT / CLEAN COPY Hypospadias in the Offspring[END_REF] A similar work in the south of France (95 newborns with cryptorchidism and 188 controls born between 2002 and 2005) showed a higher risk of having a child with cryptorchidism among mothers who reported using products containing phthalates in the workplace, before and during pregnancy. [START_REF] Wagner-Mahler | Prospective study on the prevalence and associated risk factors of cryptorchidism in 6246 newborn boys from Nice area, France[END_REF] These results nonetheless concern retrospective studies that must be confirmed by prospective studies. A Chinese cohort study of 9710 pregnant women also found a higher risk of small-for-gestational-age children among women using cosmetics for the face (eg, makeup, ACCEPTED MANUSCRIPT / CLEAN COPY lotion, and creams) after adjustment for confounding factors (OR, 1.23; 95% CI, 1.04-1.44).

The risk increased with frequency of use, reaching an OR of 1.83 (95% CI, 1.25-2.69) among women who reported use exceeding 5 times a week. [START_REF] Li | Maternal cosmetics use during pregnancy and risks of adverse outcomes: a prospective cohort study[END_REF] Several meta-analyses have reviewed studies of phthalate exposure (in particular, DEHP and BPD) during pregnancy. These substances were associated with an excess risk of preterm birth, reproductive impairment (reduced anogenital distance, hypospadias, and cryptorchidism), low birth weight, [START_REF] Marie | Obstetrical outcomes and biomarkers to assess exposure to phthalates: A review[END_REF][START_REF] Evaluation | prévention et perception des risques en santé environnementale. Réflexions à propos de l'exposition des femmes enceintes aux phtalates et substituts[END_REF] and psychomotor developmental disorders. [START_REF] Ejaredar | Phthalate exposure and childrens neurodevelopment: A systematic review[END_REF] According to a recent literature review, these 2 phthalates, as well as several others with either short or long chains, may be capable of impairing thyroid function (decrease in FT3, FT4, T3, and T4 hormones, depending on the substance). [START_REF] Qian | The Endocrine Disruption of Prenatal Phthalate Exposure in Mother and Offspring[END_REF] The authors note that impairment of maternal thyroid function has been associated with an increased risk of preterm birth, low birth weight, and neurodevelopmental impairment in children.

A recent meta-analysis showed an association between prenatal exposure to some phenols/ketones (parabens, triclosan, benzophenone-3, bisphenol A, and dichlorophenols) and low birth weight. [START_REF] Zhong | Association of prenatal exposure to phenols and parabens with birth size: A systematic review and meta-analysis[END_REF] Several works have also examined phenoxyethanol in the PELAGIE cohort study, which included 3421 women in early pregnancy between 2002 and 2006. They were followed up through the end of their pregnancy, and their children's health status was assessed at birth, 2, 4, and 6 years. The results showed that a higher urinary concentration of phenoxyacetic acid in early pregnancy was associated with a prolonged time to conception, a probability of conception during the cycle reduced by 30% (OR, 0.70; 95% CI, 0.52-0.95). [START_REF] Garlantézec | Urinary glycol ether metabolites in women and time to pregnancy: the PELAGIE cohort[END_REF] modifications of the concentrations of several steroid hormones in the cord blood, [START_REF] Warembourg | Prenatal exposure to glycol ethers and sex steroid hormones at birth[END_REF] and reduced performance on the verbal scale of the WISC-IV (neurocognitive test) in children at the age of 6 years. [START_REF] Béranger | Prenatal Exposure to Glycol Ethers and Neurocognitive Abilities in 6-Year-Old Children: The PELAGIE Cohort Study[END_REF] Finally, a case-control study from the PELAGIE and EDEN cohorts showed that children's birth weight was inversely correlated with their mothers' early pregnancy urinary concentration of dichlorophenols and positively correlated with that of benzophenone-3. [START_REF] Philippat | Exposure to phthalates and phenols during pregnancy and offspring size at birth[END_REF] The impact of triclosan, a potentially endocrine-disrupting preservative, on fetal growth and the risk of preterm birth remains uncertain according to a systematic review, [START_REF] Khoshhali | Impact of prenatal triclosan exposure on gestational age and anthropometric measures at birth: A ACCEPTED MANUSCRIPT / CLEAN COPY systematic review and meta-analysis[END_REF] while a nearly contemporaneous US study found lower school performance (reading and mathematics) in the most strongly exposed 8-year-old children (measured by maternal urinary concentration at birth and the child's urinary concentration at one year of life). [START_REF] Papandonatos | Gestational and childhood urinary triclosan concentrations and academic achievement among 8-year-old children[END_REF] Combining the epidemiologic data with experimental findings from rodents, Leppert et al. (2020) showed an increased risk of overweight in little girls in their first 9 years of life after ACCEPTED MANUSCRIPT / CLEAN COPY maternal exposures to butyl-paraben during pregnancy, [START_REF] Leppert | Maternal paraben exposure triggers childhood overweight development[END_REF] via its action on the neurons that regulate appetite. These results as a whole suggest that some substances present in cosmetics affect reproduction and fetal and child development. They remain to be confirmed in studies that take into account some limitations of the existing studies, such as issues with exposure measurements (for example, the sometimes short half-life of the substances monitored) and the failure to adjust for co-exposures.

Household Accidents

According to a local French study, acute poisoning with cosmetic products (most often, associated with ingestion of or ocular contact by soap/shower gel, shampoos, or perfumes) accounts for 25% of bathroom poisonings. In the vast majority of cases, these accidents concern children younger than 4 years. The symptoms vary according to the type of product and type of contact (Table 2). [START_REF] Chu De | Les intoxications accidentelles de l'enfant par des cosmétiques dans la salle de bains[END_REF]

Perceptions Associated with the Use of Cosmetic Products

Several studies in France have examined perceptions of cosmetic product use by pregnant women; knowledge of the perceptions linked to the use of these products for children younger than 3 years is more limited.

Perception by Pregnant Women

Globally, women appear to be worried about the risks linked to exposure to cosmetic products during pregnancy: in the study by Marie et al. (2016), more than half the women (55%) considered cosmetics as a risk during pregnancy 9 ; Rouillon et al. (2017) reported that 91% of the women identified cosmetics as a source of endocrine disrupters. [START_REF] Rouillon | Endocrine Disruptors and Pregnancy: Knowledge, Attitudes and Prevention Behaviors of French Women[END_REF] Nonetheless, as reported above, reduction of the use of cosmetic products because of pregnancy appears to be limited. [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF][START_REF] Rouillon | Endocrine Disruptors and Pregnancy: Knowledge, Attitudes and Prevention Behaviors of French Women[END_REF] Cutting back cosmetic use did not appear to be a priority for reducing exposure to endocrine disrupters. For example, only 13% of women reported that they limited cosmetic use during pregnancy, although more than 30% reported taking other steps to limit their exposure to endocrine disrupters (verifying recycling codes, eating more foods produced by organic agriculture, eating more fresh products, reducing intake of industrial products, etc.). [START_REF] Rouillon | Endocrine Disruptors and Pregnancy: Knowledge, Attitudes and Prevention Behaviors of French Women[END_REF] In the study by Marie et al. (2016), fewer than 20% of women reduced their use of cosmetic products during pregnancy, and fewer than 10% replaced some products by others considered "less harmful." [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF] On the other hand, use of some types of cosmetic products ACCEPTED MANUSCRIPT / CLEAN COPY was reduced or even stopped during pregnancy: nail polish and polish remover, hair dyes, perfume, and deodorants. [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF][START_REF] Teysseire | Perception of Environmental Risks and Behavioral Changes during Pregnancy: A Cross-Sectional ACCEPTED MANUSCRIPT / CLEAN COPY Study of French Postpartum Women[END_REF] Moisturizing body cream was the only product used more often in pregnancyin terms of both the proportion of users and the frequency of use. [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF] During pregnancy, the principal criteria for the choice of cosmetic products were their composition and their odor. [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF] These data show that women seem to be aware of a risk associated with cosmetics; nonetheless, most modify their usage habits very little, if at all, during pregnancy. Prevention of exposure to cosmetic products is often not a priority and might be difficult to implement because of the ubiquitous even invisible nature of chemical contaminants and alternatives that are less practical and/or more expensive. 9,10 These obstacles have been observed in 2 qualitative studies in Canada. [START_REF] Ashley | Pregnant women's navigation of information on everyday household chemicals: phthalates as a case study[END_REF][START_REF] Sharma | Views of pregnant women and clinicians regarding discussion of exposure to phthalate plasticizers[END_REF] Studies also often mention the lack of information and advice provided to women during pregnancy. That is, more than 65% of women (pregnant or not) wanted advice about the use of these products. [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF] More generally, 70% of women did not consider themselves sufficiently informed about sources of environmental exposure [START_REF] Teysseire | Perception of Environmental Risks and Behavioral Changes during Pregnancy: A Cross-Sectional ACCEPTED MANUSCRIPT / CLEAN COPY Study of French Postpartum Women[END_REF] and felt that their knowledge of endocrine disrupters was inadequate. [START_REF] Rouillon | Endocrine Disruptors and Pregnancy: Knowledge, Attitudes and Prevention Behaviors of French Women[END_REF] Only a minority reported having received advice and information from health care professionals about exposure to endocrine disrupters and/or use of cosmetic products. 9,10 Nonetheless, women often perceived the health authorities and health care professionals (midwives, gynecologists-obstetricians, and general practitioners) as relevant sources of information. [START_REF] Marie | Changes in Cosmetics Use during Pregnancy and Risk Perception by Women[END_REF][START_REF] Teysseire | Perception of Environmental Risks and Behavioral Changes during Pregnancy: A Cross-Sectional ACCEPTED MANUSCRIPT / CLEAN COPY Study of French Postpartum Women[END_REF]

Perceptions by Health Care Professionals

In France, several studies have examined health care professionals' perceptions of the risks associated with cosmetic product exposure to pregnant women and children younger than 3 years. These studies agreed that globally these professionals: (1) are aware of the risks associated with cosmetic product use by pregnant women and very young children, ( 2) are asked by pregnant women about the use of cosmetic products and their risks, and (3) clearly lack adequate knowledge and tools to respond appropriately to these questions by pregnant women. [START_REF] Marie | Perception of Environmental Risks and Health Promotion Attitudes of French Perinatal Health Professionals[END_REF] There have been 3 cross-sectional investigations on this topic in France. A study conducted in 2015 in the region of Auvergne among 189 perinatal health care professionals (obstetricians, midwives, and general practitioners) showed that 37% of professionals considered the use of cosmetics by pregnant women as a risk for the health of the women and their unborn babies. [START_REF] Marie | Perception of Environmental Risks and Health Promotion Attitudes of French Perinatal Health Professionals[END_REF] Midwives and general practitioners perceived this risk more often than ACCEPTED MANUSCRIPT / CLEAN COPY obstetricians (P<.01). Among health care professionals, 20% reported that women frequently ask them about cosmetic product use; most did not feel able to answer these questions correctly.

A tiny minority of professionals (4%) advised women to reduce their use, and approximately 30% (most often midwives) recommended that they use products "without phthalates," "without parabens," and "without fragrance." [START_REF] Marie | Perception of Environmental Risks and Health Promotion Attitudes of French Perinatal Health Professionals[END_REF] In another study conducted in 2017 (Provence-Alpes-Côte d'Azur region) among 962 health care professionals (41% midwives, 26% physicians, and 16% nurses), Sunyach et al. (2018) questioned them about the topics that women most often asked them about. [START_REF] Sunyach | Environmental Health in Perinatal and Early Childhood: Awareness, Representation, Knowledge and Practice of Southern France Perinatal Health Professionals[END_REF] Among the environmental health themes, cosmetic products (including products for infants) was the topic raised most often (20%), along with pollution. Nonetheless, cosmetics are one of the topics least well understood by health care professionals. In a final study conducted in several French public and private hospitals, 57% of the professionals (midwives, obstetricians, general practitioners, and residents) reported that they provide women with no information about endocrine disruptors during pregnancy. [START_REF] Renzo | International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals[END_REF] Overall, 74% of the respondents considered that the information about the health risks of endocrine disruptors is important, and 93% wanted to be better informed.

The principal obstacles to the provision of information and advice to pregnant women shown in these studies were the professionals' lack of knowledge about cosmetic products, lack of training, the lack of scientific evidence in the area of environmental health, fear of women's reactions, and the absence of alternative solutions. [START_REF] Sharma | Views of pregnant women and clinicians regarding discussion of exposure to phthalate plasticizers[END_REF][START_REF] Marie | Perception of Environmental Risks and Health Promotion Attitudes of French Perinatal Health Professionals[END_REF][START_REF] Sunyach | Environmental Health in Perinatal and Early Childhood: Awareness, Representation, Knowledge and Practice of Southern France Perinatal Health Professionals[END_REF][START_REF] Marguillier | Endocrine disruptors and pregnancy: Knowledge, attitudes and practice of perinatal health professionals. A French multicentre survey[END_REF][START_REF] Albouy-Llaty | Environmental Health Knowledge, Attitudes, and Practices of French Prenatal ACCEPTED MANUSCRIPT / CLEAN COPY Professionals Working with a Socially Underprivileged Population: A Qualitative Study[END_REF]

Studies of Interventions to Reduce Exposure to Some Cosmetic Ingredients Considered

Suspect

The studies described above suggested that increased cosmetic product use was associated with higher exposure levels to some compounds in adults, specifically, phenols, parabens, plasticizers, and phenoxyethanol. Logically, reducing cosmetic use should reduce these exposures (LE2). In the interventional study by Harley et al. (2016), the authors replaced the usual cosmetic products of 100 young women with those certified to contain no phthalates, parabens, triclosan, or 3-benzophenone (LE2). [START_REF] Harley | Reducing Phthalate, Paraben, and Phenol Exposure from Personal Care Products in Adolescent Girls: Findings from the HERMOSA Intervention Study[END_REF] Three days after this intervention, urinary concentrations of 3 phthalate metabolites fell by 27%. Similar results were obtained for the measurements of triclosan (-35.6%) and 3-benzophenone (-36%). The results for parabens were more divergent. Hagobian et al. (2016) set up a pilot interventional study among 24 women, aimed at reducing their exposures to bisphenol A. [START_REF] Hagobian | Randomized Intervention Trial to Decrease Bisphenol A Urine Concentrations in Women: Pilot Study[END_REF] The women selected (by randomization) for the intervention participated in a weekly face-to-face interview aimed at informing them about sources of chemical exposures; they also received one batch of cosmetics and food ACCEPTED MANUSCRIPT / CLEAN COPY storage boxes without bisphenol A. The authors observed a mean decrease of 45% in this chemical's urinary concentration among women who underwent the intervention (LE2).

Finally, in a US cohort study of 656 women, Serrano et al. (2014) reported that urinary concentrations of MEP (monoethyl-phthalate, a metabolite of diethyl-phthalate, used in cosmetics) was 54% (95% CI, 17%-102%) higher among women who reported that they only rarely used "environmentally-friendly" products (LE2). [START_REF] Serrano | Dietary phthalate exposure in pregnant women and the impact of consumer practices[END_REF] This article suggests an interest in eco-responsible labels to reduce user exposure.

DISCUSSION

Cumulative Exposure

It is important to remember that cosmetic products on the market have been assessed for their absence of known risk to consumers. Nonetheless, as mentioned in European regulations, safety is evaluated individually for each product. No cumulative exposure has yet been assessed, except for the ingredients used as preservatives. [START_REF]Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation -10th Revision[END_REF] Many of these ingredients can be found not only in numerous distinct cosmetic products but also in other sources of exposure, such as food or cleaning products (presence of phthalates, parabens, etc.). [START_REF] Martina | Lifestyle behaviors associated with exposures to endocrine disruptors[END_REF][START_REF] Marie | Obstetrical outcomes and biomarkers to assess exposure to phthalates: A review[END_REF] Cosmetic products may also be contaminated by substances used in the composition of their container. This is especially true for containers made of polyvinyl chloride, for which authors have shown that components such as phthalates are likely to be released from the container and migrate toward the contents. [START_REF] Bernard | Migrability of PVC plasticizers from medical devices into a simulant of infused solutions[END_REF][START_REF] Murat | Identification of Potential Extractablesand Leachables in Cosmetic Plastic Packagingby Microchambers-ACCEPTED MANUSCRIPT / CLEAN COPY Thermal Extraction and Pyrolysis-Gas Chromatography-Mass Spectrometry[END_REF] Overall, the average number of cosmetic products used daily is 18 for pregnant women and 6 for children younger than 3 years. [START_REF] Ficheux | Consumption of cosmetic products by the French population. First part: frequency data[END_REF][START_REF] Ficheux | Consumption of cosmetic products by the French population second part: Amount data[END_REF] Cumulative exposure to different products could therefore theoretically result in exposure that exceeds health safety thresholds for some of their shared ingredients. To overcome this problem, the principal recommendations to be made to pregnant women and parents of young children should be to limit the frequency of use and the quantity applied at each use, and to prefer, for identical effects, the products containing the fewest possible ingredients. In addition, risk assessments should be conducted to assess this cumulative exposure, or even the potential synergistic effect of some compounds that act with similar mechanisms of action. [START_REF] Kortenkamp | Low dose mixture effects of endocrine disrupters: implications for risk assessment and epidemiology[END_REF]

Certification of Cosmetics

Certification is available for cosmetics. Nonetheless, the number of existing labels (Ecocert, Cosmebio, Ecolabel, Demeter, Natrue, etc.) as well as their criteria (nature and origin of the ACCEPTED MANUSCRIPT / CLEAN COPY ingredients used, environmental impacts, animal well-being, etc.) can complicate the choices for users. Moreover, the labels do not all have the same requirements.

Here, the principal criterion of some of the labels is the nontoxicity of their ingredients (use of animal testing is not considered here). The table presented as an appendix (Appendix 1) is therefore not exhaustive but offers a synthesis of selected labels, including French (Cosmebio, Ecocert), European (Nature & Progress, Cosmos, Ecolabel) and international (Natrue) labels.

COSMOS is the label most recently standardized at the European level, in 2017; there are 5 relevant European labels including Ecocert and Cosmebio. These labels are mainly distinguished by the percentage of ingredients of natural or organic origin as well as by the ingredients banned in cosmetic products. Most of the cosmetics called "natural" or "organic" contain a maximum of ingredients of plant origin and limit as much as possible the synthetic agents considered undesirable. As of today, there is no legal definition of natural or organic cosmetics; we can talk instead of natural and organic sources of these ingredients. An ingredient of natural origin can come from an animal, plant, or mineral and can have been transformed, principally by primary mechanical and chemical processes such as distillation, cooking, mechanical filtering, fermentation, and oxidation. It cannot, however, have undergone extensive chemical or technological manipulations that consume excessive quantities of energy, are polluting, and which abusively or totally modify the original component. Ingredients of organic origin correspond to raw materials cultivated or harvested according to certified organic methods. The official label of the European Union (Ecolabel) is presented in this table, but it must be noted that it sets no requirements about the nature or origin of the ingredients used. It is also important to note that an ingredient's natural origin does not guarantee its lack of toxicity. This label essentially considers the environmental impact of products, emphasizing their nontoxicity for the environment throughout their life cycle (design, production, marketing, and use, and information to consumers).

Essential Oils and Artisanal Preparations

In the French study by Cabut et al. (2017), a relatively high proportion of women (18%) reported using essential oils during pregnancy. [START_REF] Cabut | Intended and actual use of selfmedication and alternative products during pregnancy by French women[END_REF] The ANSM and the ANSES (Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail, national agency of health security for food, the environment, and the workplace) nonetheless point out that any use of essential oils, particularly in pregnant women and children, requires prior medical advice insofar as some of them may present a risk of toxicity. [START_REF]Sprays et diffuseurs à base d'huiles essentielles à usage domestique[END_REF][START_REF] Ansm | Médicaments à base de plantes. Les huiles essentielles[END_REF] Essential oils contain elevated quantities of phenols, ketones, and phenylpropanoids. They can, for example, increase the risk ACCEPTED MANUSCRIPT / CLEAN COPY of miscarriage, especially during the first trimester of pregnancy. [START_REF] Tillett | The uses of aromatherapy in women's health[END_REF] The safety during pregnancy of most essential oils has not been evaluated.

It is also important to note that artisanal preparations of cosmetics are not at all certified and must be considered with prudence, in particular during pregnancy and in young children. For example, the manufacture of handcrafted oleo-limestone liniment can induce a risk of burns if done improperly as well as a risk of spoilage because of the absence of preservatives.

Baby's Buttocks

The French study by Ficheux et al. (2016) about caring for the baby's buttocks showed that use of wipes is widespread (64%). [START_REF] Ficheux | Consumption of cosmetic products by the French population second part: Amount data[END_REF] Oleo-limestone liniment and cleansing water were used less often (33% and 29%, respectively). The use of wipes has been quite controversial for several years now, since these products are most often unrinsed and contain numerous chemical substances (preservatives, perfumes, etc.). [START_REF] Vallée | Les soins du nourrisson : de la toilette à l'hydratation. Utilisation et comparatif des gammes de cosmétiques disponibles en pharmacie d'officine[END_REF] Oleo-limestone liniment is a mixture of extravirgin olive oil and limewater. Nonetheless, many products are marketed with additional components such as preservatives and emollient or protective substances. Moreover, the liniment must not be considered a detergent because it has no surfactants. [START_REF] Vallée | Les soins du nourrisson : de la toilette à l'hydratation. Utilisation et comparatif des gammes de cosmétiques disponibles en pharmacie d'officine[END_REF] Its use must therefore be combined with the use of a mild detergent product (water with appropriate soap).

Smartphone Applications

The recent acceleration of smartphone application development has made it possible to scan or analyze cosmetic products, to list the ingredients present, and identify those that may be toxic.

These apps make it possible to increase consumers' awareness of the risks associated with cosmetics. Some also offer epidemiologic data (references available about the use of different cosmetics). Nonetheless, these must not be considered a complete source of information and must be used prudently. Most of them were not developed by professionals in cosmetic formulation and thus lack toxicological expertise. Possible errors by the technology used (text detection in a photo, for example) could result in failure to consider potentially harmful ingredients. These databases might be neither complete nor routinely updated when the composition of products is modified. The information provided is often simplified and summarized by a rating (good, poor, limited risk, average risk, etc.). Moreover, these ratings are essentially based on the list of ingredients, without any consideration of quantities. Some apps also offer alternatives labelled without risk, but without explaining the selection criteria applied.

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RECOMMENDATIONS

A synthesis of these guideline are presented elesewhere. [START_REF] Barasinski | Intervention during the Perinatal Period: Synthesis of the Clinical Practice Guidelines from the French National College of Midwives[END_REF]

General Recommendations

-Reduce the number (grade B), frequency of use (grade B), and quantity applied (expert consensus) of all cosmetic products used by women in the perinatal period for themselves, but also for their children (grade B).

-Prefer simple products, with a short list of ingredients, without perfume, and rinsable (expert consensus).

-Avoid the use of essential oils (expert consensus).

-Products with trustworthy ecolabels (eg, Cosmebio, Ecocert, Nature & Progress, Cosmos, Natrue) can be preferred (expert consensus).

-Smartphone apps can be used by women, once they have been informed of the value of reducing cosmetic use and of the apps' limitations (expert consensus).

Pregnant and Breastfeeding Women

-Avoid the use of perfumes, nail polish/remover, and hair coloring (expert consensus).

-Air out rooms after the use of volatile cosmetic products, especially sprays and aerosols (expert consensus).

Children Younger than 3 Years

-For children, avoid industrial wipes (containing a large number of ingredients and not rinsable). Prefer water and an appropriate soap if needed (expert consensus).

-When necessary, use cosmetic products intended for children younger than 3 years (expert consensus).

As for all possibly toxic products:

-Store cosmetics in a safe place, either high up, or in a locked closet (expert consensus) -Should they be ingested, it is recommended to call the poison center, which can best evaluate the management needed according to the type and quantity of products ingested. In the case of serious events, call emergency medical services (expert consensus)

From-

  Abbreviations: GMO, Genetically modified organisms

Table 2 . Examples of Symptoms Linked to Toxicity from Cosmetic Products

 2

	ACCEPTED MANUSCRIPT / CLEAN COPY

Acknowledgments

The authors thank: the coordinators (Chloé Barasinski, Clermont-Ferrand; Rémi Béranger, Rennes; Catherine Salinier, Gradignan; Cécile Zaros, Paris) and the experts in the working

Funding:

These clinical practice guidelines were funded by the French National College of French Midwives.

License:

This is an Open Access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2020 the Authors.

Tables and figures


Nicolas Dheilly
email: nicolas.dheily@insa-lyon.fr

Gontran Pâques
email: bgontran.paques@isl.eu

D Planson

P Bevilacqua
email: dpascal.bevilacqua@insa-lyon.fr

S Scharnholz
email: esigo.scharnholz@isl.eu

Optical triggering of 4H-SiC thyristors with a 365 nm UV LED

Keywords: 4H-SiC, thyristor, optical triggering, UV LED

Direct light triggering of 4H-SiC thyristors with a 365 nm UV LED was demonstrated. Two different structures with etched and non etched gate were successfully tested. The current rise time was less than 100 ns and the delay time as short as 1.5 μs. The optical energy density necessary to switch-on a thyristor has been studied for different optical power density and bus voltages. This work shows that the UV LED technology is becoming sufficiently powerful to switch-on SiC thyristors. Thus, an alternative, less expensive and more compact gate light source than UV laser is now possible. This can be of particular interest for very high voltage and pulse power electronic applications.

Introduction

The use of 4H-SiC thyristors is of specific interest in pulse power applications [1] to increase the power density and to reduce the number of devices connected in series. In such systems, the isolation of the driver and the electromagnetic interferences are serious issues. Direct light triggering of thyristors can solve these problems [START_REF] Schulze | 11th EPE[END_REF]. The switch on of SiC thyristor with a 337 nm UV laser pulse has already been shown in [START_REF] Levinshtein | [END_REF]. The development of the UV light-emitting diode (LED) technology in the past few years has resulted in the commercialization of numerous devices. 4H-SiC thyristors with a simple mesa termination were fabricated to evaluate their sensitivity to optical switch-on with UV LED.

Device Fabrication

About 50 thyristors, with an active area ranging from 0.18 to 1.5 mm 2 , were fabricated on two 1 × 1 cm 2 samples. The n-type 4H-SiC substrate covered by 4 (P/P-/N/P+) epilayers is the same as used for the thyristors presented in [4]. Fig. 1 shows the cross-section of the thyristors and indicates the epi-layer specifications as given by the material supplier. A 5.5 μm mesa termination was first etched by a RIE process using a nickel mask. The simulated protection efficiency of this termination is rather poor (25%) but the objective was here to evaluate only the optical turn on. One of the two sample was then etched a second time (indicated by the dashed line in Fig. 1) to open the gate layer. On the second sample the top P+ layer remains unopened. Al/Ti/Ni and Ti/Ni metal layers for the anode and the cathode were formed by lift-off and annealed at 1000°C to get ohmic contacts. A 500 nm thick overmetallization for the anode contact (Ti/Ni/Au) was finally deposited. All metallizations were realized by electron beam evaporation.

TLM measurements after the over-metallization reveal a specific resistance of the anode contact in the range of 3 -9 × 10 -4 Ω•cm 2 . Forward blocking voltage for a leakage current of 1 μA was measured in vacuum. Some thyristors were able to sustain a forward voltage in excess of 1100 V. The two samples were finally attached on an alumina substrate with silver paste and bonded with 50 μm diameter gold wire.

Experimental Set-up

A 365 nm UV LED with a spectrum half width of 9 nm and a nominal optical power output of 250 mW was used to switch on the thyristors. Its wide emission angle of 120° was narrowed using a ball lens (see Fig. 2). The position of the device could be set quite precisely in the X, Y and Z directions. The optical power of this light source was measured through a 1 mm diameter hole. To perform these measurements, the hole was moved to the position of maximum power. The optical power was found to rise linearly with the LED current in the range of 0.1 A to 1 A. Over this range and for a useful lightening area corresponding to the 1 mm diameter hole, the power yield of the optical system as a whole is between 1% and 2 %. The yield of an individual 365 nm LED is between 10 and 15 %, according to the technical data-sheet. Before the measurements presented in the next section, the position of the SiC thyristor was adjusted to the maximum optical power point, using its photo-current as indicator. As shown on Fig. 3, the switching characteristics of the thyristors were studied with a resistive load.

Results

Switch-on behavior. Thyristors on both etched gate and non etched gate samples were able to be turned on. This is explained by the quite long penetration depth of UV light in SiC for these wavelengths. Indeed, the penetration depth is around 125 µm [5] for a wavelength of 365 nm, which is much longer than the thickness of all epi-layers of the thyristor. A light source with a shorter wavelength would have been more suitable, but the yield and the output power of such UV LEDs are quite low. The structure without gate etching will be preferred when designing new light triggered thyristors (LTT), because the process is a little simpler and the current homogeneity is supposed be better with the P+ layer covering the entire active area.

A typical switching waveform is plotted in Fig. 3. The current of 1.3 A after turn-on corresponds to a current density of 370 A.cm -2 . The switching was very fast with a rise time of about 40 ns. All Optical power density. From the LED current measurements one can deduce the optical power density at the thyristor surface using the previous characterization of the diode (section "Experimental Set-up"). The optical energy density necessary to turn-on the thyristor can then be estimated by multiplying the power density by the delay time. The dependence of this energy density on the power density at the surface of the thyristor is shown in Fig. 5.

Over the power range covered by the light source, the energy density Eon required to switch on the device decrease with the optical power density. The lowest optical energy density used to turnon this device was 1.1 × 10 -5 J.cm -2 . This value is close to the value of 1.0×10 -5 J.cm -2 from [START_REF] Levinshtein | [END_REF], which was measured using a 337 nm, 7 ns laser pulse. Eon for an electrical triggering of SiCthyristors fabricated on the same material is around 8 × 10 -6 J.cm -2 . This value has been obtained with the data given in [4] and assuming an anode gate voltage of 3 V. Thus, the energy density necessary to turn on the thyristor is approximately the same for optical and electrical triggering. Nevertheless, considering the efficiency of the optical system used, light triggering of SiC-thyristors still requires approximately 2 orders of magnitude more energy than electrical triggering. However, this energy is still low compared to the energy that the thyristor can handle. Furthermore, Fig. 5 shows that Eon and consequently the delay time decrease with an increasing bus voltage. This is to be explained by the space charge region expanding with the bus voltage which means that the amount of optically generated carriers that are separated by the electric field increases. Therefore, the equivalent gate current becomes higher. Moreover, as the space charge expands, the drift layer length on which the carrier have to diffuse becomes shorter. This accelerates the transport of the carriers through the drift layer, and thus the turn-on process. On the other hand, figure 5 shows that Eon does not decrease significantly when the bus voltage moves from 400 V to 500 V. A possible explanation is that the drift layer was already fully depleted at 400 V. Considering the epi-layer specifications given in the Fig. 1, an anode cathode voltage of 400 V should theoretically result in a depletion layer width of about 30 µm. This is in contradiction with the previous supposition. So, C/V measurement between the anode and the cathode were performed, revealing that the capacitance reaches its minimum at about 360 V and keeps the same value for higher voltage. This implies a full depletion of the drift layer at 360 V. This is in accordance with our delay time measurements. As a result, the real drift-layer seems to be much thinner than the specification.

Conclusion

4H-SiC thyristors were successfully triggered with a 365 nm UV light-emitting diode. The delay time and the rise time are comparable with those of electrically triggered thyristors. However, due to the losses in the optical system (LED and lens), the energy required to turn-on the thyristor is much higher for optical triggering than for electrical triggering. Moreover, the wavelength of the UV LED is not optimal because the penetration depth is much longer than the epi-layers thickness, but commercially available LEDs with shorter wavelengths are less efficient and less powerful. The near UV-light allows also the use of optical fibre with low attenuation. Based on the results attained, a second generation of LTT is under development to evaluate the pulse current capabilities of such devices.

Fig. 1 .

 1 Fig. 1. Schematic cross section of the device structure. Dashed lines represent the gate etching on one of the two samples.

Fig. 2 .

 2 Fig. 2. Photography of the experimental set up showing the UV light source and the wire bonded thyristor devices.

Fig. 3 .

 3 Fig. 3. Simplified circuits of the experiment.

  devices show always a rise time shorter than 100 ns. The delay time between the beginning of the current pulse in the LED and the switch-on of the thyristor was measured for several bus voltages and LED currents. The LED current pulse was 50 μs long. The shortest delay time of 1.5 μs was measured with the maximum power of our light source. The values reported in the literature for electrically triggered thyristor (ETT) are typically in the range of 0.1 µs -2 μs[START_REF]The First Demonstration of the 1cm x 1 cm SiC Thyristor Chip[END_REF][START_REF] Sugawara | 12.7kV Ultra High Voltage Sic Commutated Gate Turn-off Thyristor : SICGT[END_REF][8].

Fig. 4 .

 4 Fig. 4. Current and voltage switch-on waveforms of a 0.35 mm 2 thyristor. The load was a 280 Ω resistor.

Fig. 5 .

 5 Fig. 5. Optical energy density Eon required to switch on a 0.35 mm 2 thyristor versus the optical power density Pon for different bus voltages Vbus. Eon is estimated by multiplying Pon by the delay time.

Acknowledgement

The authors would like to thank the French-German University (DFH/UFA, G2R-FA-106-07), and the French Defence Procurement Agency (DGA) for the partial financial support


Katerina Bretosh

Mathieu Beaucamp

Florine Toulotte

Jinyi Yuan

Philippe Hapiot

Maël Penhoat
email: mael.penhoat@univ-lille.fr

Bretosh Katerina

Beaucamp Mathieu

Toulotte Florine

Yuan Jinyi

Hapiot Philippe

Penhoat Maël

Mediated formic acid flow fuel cell (MFAFFC) based on biomimetic electrolytes

Keywords: biomimetic, direct formate flow fuel cell, non-noble metals, folic acid, alloxazine

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Over the past decades, new technologies based on flow electrolytic cells have opened the way of liquid phase fuels for energy conversion (formic acid/formate [START_REF] Rees | Compton Sustainable energy: a review of formic acid electrochemical fuel cells[END_REF], [START_REF] An | Direct formate fuel cells: A review[END_REF] , ethanol [START_REF] Yaqoob | Iqbal A comprehensive and critical review of the recent progress in electrocatalysts for the ethanol oxidation reaction[END_REF] , methanol [START_REF] Zuo | Li Direct methanol fuel cells system-A review of dual-role electrocatalysts for oxygen reduction and methanol oxidation[END_REF] , …). Recently, the rapid development of redox flow batteries devices permits todays to envisage new technologies and approaches in order to limit the usage of rare earth metals at electrodes [START_REF] Sánchez-Díez | Ferret Redox flow batteries: Status and perspective towards sustainable stationary energy storage[END_REF] . Even if these new approaches still need some more research studies before becoming competitive with already mature hydrogen fuel cells technologies, they are already emerging as alternatives to reduce the security limitations encountered with hydrogen storage.

Additionally, the search for low-cost devices have reinforced such developments.

In the large set of possible liquid fuels, formic acid (FA) appears of high interest for its high volumetric energy density, its open circuit voltage (OCV, 1.40 V) [START_REF]Demirci Theoretical means for searching bimetallic alloys as anode electrocatalysts for direct liquid-feed fuel cells[END_REF] , its high theoretical energy efficiency [START_REF] Yuan | PEM Fuel Cell Fundamentals[END_REF] , and its better safety compared to the traditional hydrogen. If the volumetric energy density of FA is significantly lower than methanol, higher concentrations of FA can be used because of the lower crossover through the polymer electrolyte membrane [START_REF] Rhee | Masel Crossover of formic acid through Nafion® membranes[END_REF] . As other advantages, FA is relatively safe with low flammability under ambient conditions. If all these technologies are particularly promising and efficient, they require large quantities of rare earth metals such as platinum, iridium or palladium as electrocatalysts, to permit the direct conversion at the electrodes of all these fuels into protons and electrons. If those metals would have been more abundant at lower prices, it is probable that such technologies would have already been the definite alternative to oil world consumption since those fuels can easily be regenerated from biomass or CO2 recycling [START_REF] Ma | Boffito From CO2 to Formic Acid Fuel Cells[END_REF] . For this reason, the quest for other electrocatalytic systems is also a nowadays challenge.

In this study, we focused in evaluating some aqueous bioorganic molecules and their derivatives (Figure 1, X) as FA oxidant, in order to build a spontaneous mediated formic acid flow fuel cell process (MFAFFC) by transporting ACCEPTED MANUSCRIPT / CLEAN COPY its two protons and two electrons (Figure 1, XH2) to the anode. Such new system has never been described in literature and modifies the way of converting formic acid to electricity compared to classical indirect formic acid fuel cells or direct formic acid fuel cells. In this system, redox properties (kinetic and thermodynamic) will be governed by a low cost and abundant organic electrolyte. One major advantage of aqueous organic electrolytes is their high redox activity at low cost carbon electrodes. In the present study, we propose to introduce a new liquid phase electrochemical cell process deriving from redox flow batteries in order to remove rare earth metals from both anode and cathode for formic acid conversion into electricity. A rapid survey of literature indicates that in the human body, three B vitamins are implicated in the formic acid metabolism based on redox pathways for methylation reaction (Riboflavin -B2 Vit., Folic Acid -B8 Vit, Cobalamin B12 Vit.) [10][11] . At this stage, we hypothesized the ability of these molecules (X) to oxidize formic acid into CO2 and being reduced in the form of XH2 similar to the reduced forms suggested in most of electroanalysis articles [12][13] . This reduction pathway being the active pathway at the carbon anode of a flow fuel cell as recently observed for redox flow batteries for Riboflavin [START_REF] Orita | A biomimetic redox flow battery based on flavin mononucleotide[END_REF] . We limit the list of possible candidates to Riboflavin and Folic Acid for their low cost in the preview of eventual larger scale evaluation. In a previous study, we have demonstrated that Riboflavin can be degraded when acting as a photochemical fuel [START_REF] Lin | Penhoat Riboflavin as a Bioorganic Solar Fuel: Photoredox Chemistry Rationalized and Accelerated in a Miniaturized Flow Photoreactor[END_REF] leading us to focus our effort on its natural degradation side product the Lumichrome to produce biomimetic models. In this context, since Lumichrome is not water soluble, we envisaged, according to a procedure already described in literature by Janáky and Rajeshwar [START_REF] Kormányos | Electrocatalytic behavior of freelydiffusing and immobilized synthetic flavins in aqueous media[END_REF] , to add ammonium chains on the two acidic nitrogens of alloxazine skeleton in order to increase their water solubility and as a consequence their overall fuel cell capacity.

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Materials and methods

General information

All reagents were purchased from commercial suppliers (Strem Chemicals Inc., Sigma-Aldrich or Alfa Aesar) and were used without further purification. DMF (Fisher Scientific, Illkirch, France) was stored with active molecular sieves (3 Å) for 24 hours before usage. Water used was MilliQ grade. Thin-layer chromatography (TLC) were performed on Silica gel 60 F254 plates (Merck, Fontenay-sous-Bois, France) and visualized under UV (254 nm) or by staining with potassium permanganate or phosphomolybdic acid. NMR spectra were recorded on a Bruker (Wissembourg, France) AVANCE 300 spectrometer at 300 MHz for 1 H and 75 MHz for [START_REF] Vladislavić | Brinić Sensitive Electrochemical Determination of Folic Acid Using ex-situ Prepared Bismuth Film Electrodes[END_REF] C. Gas emission measurements were performed with Dräger X-am® 5000 gas detector for H2, CO2, CO.

General procedure for the synthesis of electrolytes 3a and 3b:

Step 1: To a solution of O-phenylene diamine 1a or 4,5-dimethyl-1,2-phenylene diamine 1b (1 equiv. 10 mmol) in acetic acid (400 mL) under inert atmosphere, Alloxane (1 equiv.) and boric acid (1,1 equiv.) are added. The solution is maintained at room temperature for 3 h. The resulting precipitate is filtered and washed with acetic acid, diethyl ether and water to yield benzo[g]ptéridine-2,4(1H,3H)-dione (2a) (97%) and 7,8diméthylbenzo[g]ptéridine-2,4(1H,3H)-dione (2b) (96%).

Step 2: In a 25 mL flask, benzo[g]ptéridine 2a or 2b (1 equiv., 8.3 mmol) is dissolved in DMF (15 mL) and K2CO3

(2.1 equiv. 17 mmol) is added. The solution is heated under inert atmosphere at 110 °C for 3 h. The resulting precipitate is filtered and washed with DMF. Next, the precipitate is added to a solution of (2bromoalkyl)trimethylammonium bromide (2.1 equiv., 17 mmol) in DMF (15 mL) in a 25 mL flask. The resulting solution is maintained à 60 °C for 24h under inert atmosphere. The dark yellow precipitate is filtered and washed with diethyl ether and acetone to yield the 5,5'- (2,4-

dioxobenzo[g]ptéridine-1,3(2H,4H)-diyl)bis(N,N,N- triméthylpentan-1-ammonium) bromide (3a) (80%) or 2,2'-(7,8-dimethyl-2,4-dioxobenzo[g]ptéridine- 1,3(2H,4H)-diyl)bis(N,N,N-triméthylethanammonium) bromide (3b) (71%).

Scheme 1. Electrolytes 3a and 3b synthetic pathways

General procedure for electrochemical characterization of species 3a, 3b and folic acid (5).

To a 20 mL water-jacketed reactor (T = 298 K), 10 mL of the analytical solution is added containing: (i) the electroactive species (3a,b and 5) (1 mM) and (ii) the supporting electrolyte (100 mM). Depending on the pH values, supporting electrolyte are Na2SO4 (pH range = 1-4), AcONa (pH range = 3-6), NaH2PO4 (pH range = 5-9) and Na2HPO4 (pH range = 7-13), final pH values are obtained with little additions of 1 M sodium hydroxide or sulfuric acid solutions. A 3-electrodes system is used (Working Electrode (WE) = 1 mm glassy carbon, Auxiliary

1) K 2 CO 3 (2.1 equiv.) DMF, 110 °C, 3 h (2.1 equiv.) Boric acid (1.1 equiv.) Acetic acid, 3 h R.T. R = H (1a) = Me (1b) Br - 2) DMF, 60 °C, 24 h R = H (2a) = Me (2b) R = H (3a) = Me (3b) Br - Br - ACCEPTED MANUSCRIPT / CLEAN COPY Electrode (AE) = Pt wire, Reference Electrode (RE) = AgCl/Ag) to perform Differential Pulse Voltammetry (DPV)
with Metrohm PGSTAT 128N potentiostat/galvanostat. Peak potentials Ep were directly considered for evaluating the formal redox potential E°'. The reference (RE) potential is regularly checked using ferricyanide/ferrocyanide couple [START_REF] Reilly | Oxidation-reduction potential of the ferro-ferricyanide system in buffer solutions[END_REF] . During DPVs, voltage step was 1 mV and pulse amplitude 10 mV.

Description of the experimental

Results and discussion

In a prior step, the objective was to synthesize two water soluble derivatives of alloxazine skeleton 3a and 3b as biomimetic models of Riboflavin and to evaluate their properties as formic acid oxidant. Lumichrome and most of its alloxazine derivatives are not water soluble. In order to improve their solubility (up to 0.1M), we introduced on the molecules two arms composed of a C5 carbon chain and prolonged with a trimethyl ammonium function.

The C5 carbon chain demonstrated to present a higher stability versus basic conditions and drastically reduces Hoffman elimination with shorter carbon chains, also the usage of bromide counterion is privileged for similar reasons [18][19] .

As an important observation, the reaction between formic acid and isoalloxazines results in a strong gas production. The characterization of the gas composition evidences the formation of carbon dioxide as a single emitted gas and no hydrogen, nor carbon monoxide production were defected showing a unique redox pathway.

Simultaneously, NMR spectroscopy shows a complete reduction of 3a ring in the presence of formic acid (Fig. 5).

Similar gas production was observed with 3b and folic acid (5). All reactions appear spontaneous and we can reasonably confirm for these three molecules the formation of a reduced form incorporating the 2 hydrogens from formic acid at acidic/neutral pH. In basic medium, 1 H NMR study was rendered difficult due to partial deprotonation and important shifting of every signals.

ACCEPTED MANUSCRIPT / CLEAN COPY Electrochemical properties of 3a and 3b have been investigated at various pH using DPV, in order to identify formal potentials E' 0 . This method is often more precise than cyclic voltammetry [START_REF] Richardson | Determination of E20-E10 in multistep charge transfer by stationary-electrode pulse and cyclic voltammetry: application to binuclear ruthenium ammines[END_REF] . The peak potential 𝐸 𝑝 is related to the half-wave potential 𝐸 1 2 ⁄ and pulse amplitude ∆𝐸, and 𝐸 1 2 ⁄ is assimilated to the formal redox potential when diffusion and activity coefficients (𝐷 and 𝛾, respectively) of the oxidized and reduced species are close (Eq. 1 and 2). By comparison with previously reported formic acid Pourbaix diagram [21][22] , the E-pH diagrams for 3a and 3b

show that both molecules are good oxidant for formic acid at every pH (Figure 5). Unfortunately, folic acid reduction on glassy carbon was too slow that DPV is no longer suitable for a redox potential estimation. Cyclic voltammetry is then performed on folic acid (5) at pH = 14 and shows a slow reversible equilibration. At this pH, folic acid appears to be good oxidant for formic acid too. (grey) taken from literature [21][22] .

In order to quantify the potential efficiency of these electroactive bioorganic molecules to effectively convert formic acid into electricity, we build two different flow fuel cells dedicated to gas or liquid catholytes to use oxygen gas as the catholyte. We modified a commercially available hydrogen fuel cell (TDM® fuel cell) in order to introduce a nitrogen degassed buffered (pH = 7) aqueous mixture of 3b at 0.1 M (0.5 mmol) concentration mixed with formic acid (5 equivalents, 2.5 mmol) at the anode. For this purpose, we replaced the graphite hydrogen flow field by one usually dedicated to methanol fuel cells and we designed a membrane electrode assembly composed of (i) carbon paper at the anode, (ii) Nafion® 117 as the membrane and carbon gas diffusion layer on which platinum (0.5 mg.cm -2 ) is deposited on surface to play the role of the cathode for oxygen gas conversion (see setup A, Fig. 2). After pre-activation of the MEA in boiling water for 8 hours, and after the end of CO2 bubbling, the resulting anolyte preparation is pumped at 10 mL.min -1 in the flow fuel cell without any leakage observed and oxygen gas is introduced at the cathode. The voltammetry characterization of the cell was ACCEPTED MANUSCRIPT / CLEAN COPY then realized by applying a progressive current discharge and by monitoring the voltage. Such approach is conventional and permits to evaluate the maximum power density delivered by the system (for an example of such curve see figure 6). Despite a low open current voltage at 0.44 V which could be explained by a very a high resistance and/or high activation losses (i.e. low overall kinetics) of our system, the results validated the ability to produce electricity by this innovative method (Table 1, entry 1). However, the power density was low with a maximum value at 0.69 mW.cm -2 . The limited characteristics of this system could probably be ascribed to the cathode and the usage of gas phase. To check that explanation, we used a liquid catholyte for comparison instead of the oxygen cathode. In that particular case our system is very similar to a redox flow battery (RFB) process, for which the charge step is replaced by a spontaneous chemical reduction by formic acid of the anolyte. In order to evaluate this approach, we introduced two porous carbon felt electrodes (1 cm -2 ) in the electrode's volumes of a commercially available C-Flow® Lab 1×1 cell (see setup B, Fig. 3). In this system the same anolyte preparation than for setup A (5 mL) was used but oxygen gas was replaced by a benchmark catholyte aqueous solution used in RFB for its high redox stability composed of K3[Fe (III) CN6] (0.4 M) and K4[Fe (II) CN6] (0.04 M) (11 mL) at pH = 12, playing the role of oxidant in this redox mechanism. In this process, the negative terminal remains the capacitylimiting and irreversible side. In the same way than for RFB processes, the volume of each electrolyte reservoir can be modulated to increase the fuel cell capacity, but for simplicity the two reservoirs volumes were kept identical for the all set of experiments. Our first test demonstrated much encouraging results than those obtained with setup A, with a great increase of the open current voltage to 0.715 V and a maximum power density of 3 mW.cm -2 (entry 2), demonstrating our initial assumption that aqueous electrolyte would present lower resistance. In this first experiment the Nafion® 117 membrane was pre-activated as previously by boiling the membrane for 8 hours in water and we next tried to pre-activate the Nafion® 117 membrane by boiling in NaOH (0.1 M) solution as described earlier in literature for an analog RFB process [START_REF] Lin | A redox-flow battery with an alloxazine-based organic electrolyte[END_REF] . This pre-activation method is preferable (entry 3) and we kept it for the next experiments.

In order to improve the aqueous solubility of 3b we investigated the addition of small quantities of sodium dodecyl sulfate (SDS) as a surfactant. Increasing the concentration of 3b is supposed to increase the capacity of the anolyte side. SDS clearly demonstrated a great effect on 3b solubility in water (up to 0.46 M with 10% SDS) but to our surprise the performances of the fuel cell dropped (entry 4). Cyclic voltammetry with 3b (1 mM) and progressive increased concentration of SDS (see SI) show a drop of the maximum current density. This can be explained by the formation micelles associated to our anolyte increasing the overall solubility but limiting the diffusion of the molecules at the anode. Finally, best results were obtained by replacing liquid formic acid by potassium formate (3 equivalents), its basic form which is the main specie at pH = 7 (entry 6). Indeed, under such conditions, both OCV and power densities were influenced to a maximum of 16 mW.cm -2 . This obtained result is particularly interesting since today's, formate can be produced with excellent faradic yields by carbon dioxide electro-reduction and any further optimization of this system would permit to recycle easily the produced CO2 into a fuel [START_REF] Gong | Li Structural defects on converted bismuth oxide nanotubes enable highly active electrocatalysis of carbon dioxide reduction[END_REF] . To our knowledge no such fuel cell process based on potassium formate at pH = 7 exists. Increasing the pH is also a strategy since the redox potential of 3b should decrease and the resulting OCV should be higher.

By working at pH = 7 instead of pH = 12, we effectively observed a lower OCV value with probably lesser losses since the power density dropped drastically to 3.2 mW.cm -2 (entry 8). Also, it is observed a slight increase of OCV ACCEPTED MANUSCRIPT / CLEAN COPY when using potassium formate instead of formic acid, this could be justified by a higher pH after addition of potassium formate than for formic acid addition, resulting in lower redox potentials for 3b. Study of 3a under similar conditions always gave lower OCVs and power densities (entries 5 and 7). This highlights the interest of methyl substituents on the alloxazine ring as observed in riboflavin and their electroactive role. Indeed, the natural presence of methyl substituents on 7-and 8-positions of the Riboflavin's isoalloxazine ring has been the subject of numerous discussions in literature and they are implicated in the isoalloxazine ring electron transfer by stabilizing/destabilizing each one of the redox states and consequently result in an optimized mid-point redox potential [START_REF] Lans | Medina Understanding the FMN cofactor chemistry within the Anabaena Flavodoxin environment[END_REF] . Here we can reasonably produce similar conclusions considering the important differences between 3a and 3b.

Remarkably, folic acid that can be only used at pH = 14 for reversibility reasons, is also a good candidate for potassium formate conversion into electricity since measured OCVs and power densities are from the best observed so far during this study (entry 9). Another interest for the use of this molecule for formate conversion into electricity is its very low price and its high international production scale level.

Table 1. Results with MFFAFC.

[a] Anolyte mediator and formic acid where mixed in N2 degassed buffered aqueous solution. The flow fuel cell operating at 10 mL.min -1 for the anolyte and with O2 gas as the catholyte. Optimal conditions in hand, we wanted to evaluate a full discharge of the system by chronopotentiometry. We applied a 5 mA discharge current to the system based on the conditions 3b in the presence of potassium formate at pH = 7 operated for 86.7 minutes (Fig. 6 -right panel). This means that 210 mg of potassium formate produces 0.3 mW using this system which corresponds to a 0.68 Wh.L -1 energy density at pH = 7.

Entry

Conclusion

In summary, we synthesized two derivatives of B2 vitamin presenting much higher water solubility and simplified chemical structures and we evaluated their use in fuel cells in comparison with folic acid (B8 vitamin) as formic acid oxidants under different pH conditions. All of them demonstrated to be spontaneous formic acid oxidants and this particular reactivity was confirmed by their redox properties. Indeed, all three molecules show to be able to efficiently convert formic acid (or formate) into electricity (up to 16 mW.cm -2 ) using two different fuel cells operating in liquid phase. Such process has never been described earlier and introduce a new approach for removing noble metals at the electrodes by using biomimetic mediators in the electrolyte system.

At the present stage, the optimization as only focused on a limited range of aqueous conditions and only carbon materials have been evaluated as electrodes, but we can envisage some progress in the future in order to improve their performances by changing the set-up of the fuel cell. Nevertheless, our preliminary results clearly demonstrate that methyl substituents on alloxazine ring are a key parameter for obtaining an efficient redox process. Compared to a recent reported study [START_REF] Han | Galán-Mascarós A low temperature aqueous formate fuel cell using cobalt hexacyanoferrate as a non-noble metal oxidation catalyst (2020)[END_REF] in which authors replaced Pd metal by CoFe(CN)6 complex at the formate fuel cell anode, combined with Ce 4+ as the terminal electron acceptor at a carbon felt cathode to remove noble metals, their maximum power density was lower than the ones obtained in the present study with only 8.6 mW.cm -2 . Also considering the performances of redox flow batteries, we can envisage some progress in the future of a mediated formic acid (or formate) fuel cell in order to remove noble metals from electrodes and considering the very low price of folic acid, some more work should be performed. Further work for a better understanding of these redox mechanisms is also of high importance since most of proposed biological mechanisms involve enzymes and NADH coenzymes in the oxidation process of formic acid into carbon dioxide.

Here spontaneous reaction is observed and structural similarities between these three evaluated mediators strongly suggest an important role of common pyrazine ring to (i) recognize (acid base reaction) and (ii) transform formic acid into carbon dioxide (redox reaction). The repercussion of these chemical systems in chemistry will probably be more important than expected considering the observed reactivity.

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  set-up for the mediated formic acid flow fuel cell (MFAFFC) with oxygen gas catholyte -Setup A: The flow fuel cell is composed of a commercially available TDM® fuel cell (http://www.fuelcellstore.com/) in which the original membrane electrode assembly (MEA) has been replaced by a custom 4 layers MEA composed of [Carbon cloth (Anode) / Nafion® 117 / Carbon gas diffusion layer / Pt-C 0.5 mg.cm-2 (60%) (Cathode)] (http://fuelcellsetc.com/) (see figure2). This custom MEA is clamped into two PTFE gaskets, two graphite monopolar plates (serpentine design at the anode/straight channels design at the cathode), two collecting plates and two plastic plates on which are connected 1/16" tubings for the inlet and the outlet. At the anode, the degassed electrolyte solution circulates after addition of formic acid (50 µL) to a solution of ammonium alloxazine 3b (0.1 M, 3 mL). At the cathode, oxygen gas circulates and was introduced into the straight channels by 1/16" tubing connected to a manifold, itself connected to an oxygen gas cylinder. The active surface (3.9 cm 2 ) has been calculated as the anode serpentine/carbon cloth connection surface. The total internal volume of the fuel cell at the anode is 390 µL (depth of flow field = 1 mm). All electrochemical measurements were performed using a potentiostat/galvanostat (Metrohm Autolab®, PGSTAT128N, Villebon Courtaboeuf, France).

Figure 2 .

 2 Figure 2. Schematic representation of the experimental MFAFFC setup A based on TDM® fuel cell.

Figure 3 .

 3 Figure 3. Schematic representation of the experimental MFAFFC setup B based on C-Flow® Lab 1×1 cell.

Figure 4 .Scheme 2 .

 42 Figure 4. 1 H NMR characterization of (red) formic acid; (green) reduced isoalloxazine 4a at pH = 7 in the presence of 1 equiv. of formic acid; (blue) 3a; (right insert) view of the strong CO2 gas production in the NMR tube.

Figure 5 .

 5 Figure 5. E-pH diagrams for 3a (red) and 3b (blue) and 5 (green) superimposed with formic acid Pourbaix diagram

  [b] Anolyte mediator and potassium formate where mixed in N2 degassed buffered aqueous solution. The flow fuel cell operating with degassed K3[Fe (III) CN6] solution as the catholyte. Both anolyte and catholyte were pumped at 10 mL.min -1 . Nafion® 117 membrane was pre-activated 8 h in boiling NaOH (1 M) solution. [c] Nafion® 117 membrane was pre-activated 8h in boiling deionized water instead of NaOH (1 M). [d] Sodium dodecyl sulfate (10 %) was added. [e] The catholyte for setup B was composed of a mixture of K3[Fe (III) CN6] (0.3 M) + K4[Fe (II) CN6] (0.03 M).

Figure 6 .

 6 Figure 6. (left) Polarization curve of 3b at pH = 7 using setup B at 10 mL.min -1 in the presence of 3 equivalents of potassium formate. (right) Chronopotentiometry curve at 5 mA discharge current for 3b at pH = 7 using setup B at 10 mL.min -1 in the presence of 3 equivalent of potassium formate.

Figure 1 .

 1 Schematic representations of Direct and Indirect Formic Acid Fuel Cells main approaches vs our Mediated Formic Acid Flow Fuel Cell (MFAFFC)

approach Cat. Cat. HCO 2 H CO 2 X Y 1 -Direct Formic Acid Fuel Cell: Cat. HCO 2 H YH 2 3 -This study: Mediated Formic Acid Flow Fuel Cell: 2 -Indirect Formic Acid Fuel Cell (= Hydrogen Fuel Cell): XH 2 HCO 2 H CO 2 CO 2 O 2 H 2 H 2 O O 2 H 2 O

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Acknowledgements

The authors gratefully acknowledge the Region Hauts de France and ISITE Lille for the financial support (START AIRR, H2-Switch project).