Endokrin aktive Substanzen in Sonnenschutzmitteln · 17.10.18 1 Endokrin aktive Substanzen in...

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17.10.18 1 Endokrin aktive Substanzen in Sonnenschutzmitteln Gisela H. Degen Member of SCCP / SCCS (2004 – 2016); Chair of WP CosIng (2015-2016) Now: External Expert of SCCS Member of former EFSA Scientific Committee on Hazard Assessment of Endocrine Disruptors à Leibniz Institut für Arbeitsforschung an der TU Dortmund (IfADo) E-mail: [email protected] Ardeystr. 67 ● D-44139 Dortmund ● www.ifado.de BfR Symposium „50 Jahre Kosmetik-Kommission: Wissenschaft im Dienste des Verbraucherschutzes“ 16. Oktober 2018, Berlin OUTLINE ² Endokrin Aktive Substanz / Endokriner Disruptor * Definitionen (EAS or ED ?) Wirkmodus (Mode of Action) § Regulation: Hazard- vs. Risk-based § EAS in Sonnenschutzmitteln § UV Filter § Konservierungsmittel ² Diskussion - Ausblick ² Risikokommunikation: EAS oder ED ? ² In vitro - in vivo Extrapolation * Ein Sonderfall für die Bewertung ? ! apologies for d-english

Transcript of Endokrin aktive Substanzen in Sonnenschutzmitteln · 17.10.18 1 Endokrin aktive Substanzen in...

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EndokrinaktiveSubstanzeninSonnenschutzmitteln

GiselaH.Degen

MemberofSCCP/SCCS(2004–2016);ChairofWPCosIng(2015-2016)Now:ExternalExpertofSCCS

MemberofformerEFSAScientificCommitteeonHazardAssessmentofEndocrineDisruptors

à  LeibnizInstitutfürArbeitsforschunganderTUDortmund(IfADo)E-mail:[email protected]

Ardeystr.67●D-44139Dortmund●www.ifado.de

BfRSymposium„50JahreKosmetik-Kommission:WissenschaftimDienstedesVerbraucherschutzes“16.Oktober2018,Berlin

OUTLINE

²  Endokrin Aktive Substanz / Endokriner Disruptor * •  Definitionen (EAS or ED ?)

•  Wirkmodus (Mode of Action)

§  Regulation: Hazard- vs. Risk-based

§  EAS in Sonnenschutzmitteln §  UV Filter

§  Konservierungsmittel

²  Diskussion - Ausblick ²  Risikokommunikation: EAS oder ED ?

²  In vitro - in vivo Extrapolation

*EinSonderfallfürdieBewertung?!

apologies for d-english

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EndokrineRegulation-->Sexualhormone

AssaysforEstrogen,Androgen,Thyroid*,Steroidogenesis-(EATS)Modalitiesavailable:

à  OECD2012;&EFSA2013(section4.3.2.)

Abb.ausDegenGH,2004BundesgesundheitsblDOI10.1007/s00103-004-0893-5

Schilddrüse...

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Definitions I WHO/IPCS2002

“Anendocrinedisrupterisanexogenoussubstanceormixturethataltersfunction(s)oftheendocrinesystemandconsequentlycausesadversehealtheffectsinanintactorganism,oritsprogeny,or(sub)populations.”“Apotentialendocrinedisrupterisanexogenoussubstanceormixturethatpossessespropertiesthatmightbeexpectedtoleadtoendocrinedisruptioninanintactorganism,oritsprogeny,or(sub)populations.

à an endocrine active substance [EAS]

Definitions IIAdversity ? “A change in morphology, physiology, growth, reproduction, development or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increased susceptibility to the harmful effects of other environmental influences”. WHO/IPCS EHC 240, 2009

>> Interference with components of the endocrine system or

“endocrine disruption” is not a toxicological endpoint

per se, but one of the many modes-of-action which may

result in adverse effects. WHO Report 2002

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Endokrin aktive Substanzen: Modes of Action a) Interaktion mit Hormon-Rezeptoren (agonistic, antagonistic)

b) Interferenz mit Hormon-Biosynthese, Metabolismus oder Transport

e.g. Aromatase-Inhibitors, Enzyminductors, Thyroidperoxidase Inhibitors, Agents binding to SHBG or other transport proteins

Resultieren aus zellulären Effekten (a or b) auch funktionale Veränderungen in vivo ??

Fig.fromSchugTetal.2016

Fig.fromMcLachlanJA(1993)EHP101:386-7

Pharmaceutical Drugs in Pregnancy: ‘proof of principal‘ for Endocrine disruption

Diethylstilbestrol Highly potent Estrogen and Anti-Androgen

–> “DES-Daughters“ “DES-Sons“

Danazol – potent Androgen; at 200 mg or more –> Virilisation in some female offspring **

Aminogluthetimid an Aromatase Inhibitor –> Pseudohermaphoditism in Girls *

*LeMaire et al 1972 **Brunskill 1992 cited in Hotchkiss K et al. (2008)

CONCEPT: irreversible effects upon exposure

in critical stages of development

Abbildung aus

Fabricius ab Aquapendente, De Formato Foetu, 1624

Herzog August Bibliothek Wolfenbuettel

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Regulatory ‘Arena‘ Potential Endocrine Disruptors

q  FOOD: Ingredients, Preservatives, Contaminants ... EFSA European Food Safety Authority

q  Non-Food: Cosmetics, Toys, etc. SCCS Scientific Committee for Consumer Safety

q  Occupation SCOEL

SC for Occupational Exposure Limits

q  Environment SCHEER

SC on Health, Environment & Emerging Risks

scientific criteria for their identification ?

Bisphenol A Daidzein, Genistein

Parabenes, Zearalenone

Parabenen, org. UV Filter Phthalates

‘Botanicals‘ Alkylphenols, Metals, Pharmaceuticals (OC) ... Tributylzinn; POPs; Drugs; ...

Biocides, Plant Protection products, and REACH

Examples: man-made / natural

Haz

ard

or R

isk

Ass

essm

ent ?

EU Roadmap activities: ... need to harmonize guidance on the regulation of EDs

“It is expected that the consensus reached will serve as an important basis for the development of regulatory ED criteria.“

* * * * * * * * * *

TestaiE,GalliC,DekantW,MarinovichM,PiersmaAH,SharpeRM(2013)Apleaforriskassessmentofendocrinedisruptingchemicals.Toxicology314:51-59

AutrupH,BarileFA,BlaauboerB,DegenGH,DekantW,DietrichD,etal.(2015)Principlesofpharmacologyandtoxicologygovernalsoeffectsofchemicalsontheendocrinesystem.ToxicolSci146:11-15

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Definitions WHO/IPCS Apotentialendocrinedisruptorisanexogenoussubstanceormixturethatpossessespropertiesthatmightleadtoendocrinedisruptioninanintactorganismoritsprogeny,or(sub)populations. àEASAnendocrinedisruptorisanexoge-noussubstanceormixturethataltersfunction(s)oftheendocrinesystemandconsequentlycausesadversehealtheffectsinanintactorganismoritsprogeny,or(sub)populations.àED

.Number of Chemicals:

Testing for hazard „endocrine active“ .... Longterm-studies (Reprod./Devel. Tox) are quite demanding ... andnolongerpermittedforcosmeticingredients

“The challenge“

Prioritization / Safety assessment Substances of importance ?? Exposure and potency matter

AnEDdefinedbythreecriteria:i)  anadverseeffectsinanintact

organismora(sub)population,ii)  anendocrineactivity, andiii)  aplausiblecausalrelationship

betweenthetwo.(EFSA;JRC;SCCS)

Exposition (engl.Exposure)

§  Womit?Wiehoch?Kosmetika,Nahrung,Pharmaka

§  Aufnahmepfade?dermal,inhalativ,oral

§  Weristexponiert?

AlleVerbraucher,Untergruppen

äussereExpositionund

innereExposition?

•  Absorption•  Distribution•  Metabolismus•  Elimination

WievielFremdstoff(...)gelangtzuZielstrukturen(...)?

Kinetik

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Cosmetic Ingredients* Opinions by the SCCP / SCCS

* Preservatives, UV Filter, Fragrances, others

Ø  Parabens ( several ) Ø  Triclosan Ø  ortho-Phenolphenol

Ø  Benzophenones and derivatives Ø  Homosalate Ø  4-Methylbenzylidene-camphor Ø  3-Benzylidene camphor

Ø  Polycyclic musk fragrances

Ø  Cyclosiloxanes (D4, D5) Ø  Melatonin (in hair tonic) Ø  Resorcinol Ø  Kojic acid

Endocrineactivitiesandrelatedeffectsevaluatedinrelationtoexposure...

Safety/RiskassessmentusedforRegulations:a)  onpermitteduse

levelsincosmeticproductsor..

b)  restrictions/banofaningredientwhenMOS<100orsafelevelscannotbe

defined...

UV-Filter:Somestructures,examples

Benzophenones Benzophenone-3

Dibenzoylmethanes Isopropyl-Dibenzoylmethanes(Eusolex8020)

Cinnamates Ethylhexylmethoxycinnamate

PABA para-amino-benzoicacid

Camphor 4-methylbenzylidenecamphor(Enzacamene)

Octocrylene (diphenylacrylat)

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UVFilter ITable(modified)from:KrauseMetal.(2012)Sunscreens:aretheybeneficialforhealth?AnoverviewofendocrinedisruptingpropertiesofUVfilters.IntJAndrol35:424-436

FullsafetyevaluationsforUVFiltersavailableat:https://ec.europa.eu/health/scientific_committees/consumer_safety/opinions_en

UVFilter II§  AxelstadM,HassU,KinnbergKL,BjerregardP(2013)Assessmentoftheendocrine

disruptingpotentialof23UVfilters.DanishCentreofEndocrineDisruptors

Formerreviewofdatafor7UVfiltersinanothercontext:§  HassU,ChristiansenS,AxelstadM,BobergJ,AnderssonAMetal.(2012)

Evaluationof22SINList2.0substancesaccordingtotheDanishcriteriaforendocrinedisrupters.DanishCentreofEndocrineDisruptorsBenzophenone-1,2,and3(BP-1,2and3),3-Benzylidenecamphor(3-BC);4,4‘-Dihydroxybenzophenone;4-Methylbenzylidenecamphor(4-MBC); Ethylhexylmethoxycinnamate(OMC)

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Short term testing: some examples Receptorbinding•  Blair RM, Fang H, Branham WS et al. (2000) The estrogen receptor relative

binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci 54:138-153

•  Fang H, Tong W, Branham WS et al. (2003) Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor. Chem Res Toxicol 16: 1338-1358

invitrobioassays•  Byford JR, Shaw LE, Drew MGB et al. (2002) Oestrogenic activity of parabens

in MCF-7 breast cancer cells. J Steroid Biochem Molec Biol 80: 49-60 •  Schreuers RHMM, Sonneveld E, Janssen JHJ, Seinen W, van der Burg B (2005)

Interaction of polycyclic musks and UV filters with the estrogen receptor (ER), androgen receptor (AR), and progesterone receptor (PR) in reporter gene bioassays. Toxicol Sci 83: 264-272

•  Suzuki T, Kitamura S, Khota et al. (2005) Estrogenic and antiandrogenic activities of 17 benzophenone derivatives used as UV stabilizers and sunscreens. Toxicol Appl Pharmacol 203: 9-17 &àinvivobioassays

•  Van Meeuwen JA, van Son O, Piersma AH et al. (2008) Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetic products. Toxicol Appl Pharmacol 230: 372-382

UVFilter IIIKeyaspectsinthesafetyevaluation:•  Localeffects? Systemiceffects?•  Criticalendpoint(s)–>NO(A)EL?•  Sufficient info/dataon. . . ??•  Humanexposurescenario

*****EvaluationofaneworganicUVFilterwithpoorsolubilityandverylowdermalpenetration(<1%):ScientificCommitteeofConsumerSafety(SCCS)OpiniononthesafetyofcosmeticingredientsPhenylenBis-Diphenyltriazine(CASNo55514-22-2)–S86–SubmissionII SCCS/1594/18 (publicconsultation)

Lowbioavailability(oral,dermal)!

ChecklistsforDossiersubmission:SCCS/1588/17

NotesofGuidance,latestversionof25april2016:

SCCS/1564/15

SystemiceffectsalsohighlyunlikelytooccurforinorganicUVFilter!

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Parabens:Structures–Evaluations

Skin, Liver

SCCP/0873/05, SCCP/0874/05, SCCP/1017/06, SCCP/1183/08, SCCS/1348/10, SCCS/1446/11, SCCS/1514/13

MeP, EtP safe at 0.4% & mix 0.8% BuP, PrP sum at 0.19% safe*

*Not to be used in leave-on products in the nappy area due to immature metabolism of infants < 6 months

inactive

Metabolite

Exposition (engl.Exposure) Parabene‘Default‘:KonservierungsmittelinallenProdukten(Menge:17,4g)bzw.Körperpflegeprodukten=269mg/kgKG/Tag(Erwachsene)

Paraben-GehalteimProdukt(EU-Regulation):Methyl-P/Ethyl-Pje0,4%(0,8%):1,08mgMeP/EtPperkgKG/TagPropyl-P/Butyl-P0,19% : 0,51mgPrP/BuP„„

§  Womit?Wiehoch?Kosmetika,Nahrung,Pharmaka

§  Aufnahmepfade?

dermal,inhalativ,oral

§  Weristexponiert?Erwachseneund(Klein-)Kinder

äussereExposition!

innereExposition?

•  DermalePenetration•  Metabolismus

•  Ausscheidung(HBM)

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Relatedissues...Environmental Health Perspectives 123(5): A120 (2015) FOCUS: Taking stock of personal care product safety

...

U.S. sales of “natural“ personal care products grew by an estimated 7.5% in 2014, faster than the personal care product market as a whole ...

Botanicalsascosmeticingredients

•  LinJYetal.(2008)Topicalisoflavonesprovideeffectivephoto-protectiontoskin.PhotodermatolPhotoimmunolPhotomed24:61–66

•  SilvaAPetal.(2009)Developmentoftopicalnanoemulsionscontainingtheisoflavonegenistein.Pharmazie64(1):32-5.

•  IovineBetal.(2012)Acomparativeanalysisofthephoto-protectiveeffectsofsoyisoflavonesintheiraglyconeandglucosideforms. IntJMolSci.13(12):16444-56.

•  ....

Phyto-estrogensfortopicalapplication

SomeexamplesØ  ß-Arbutin àSCCS/1552/15Ø  Lawsoniainermis(Henna) àSCCS/1511/13Ø  Indigoferatinctoria àSCCS/1439/11Ø  Tea-treeoil àSCCP/1155/08

AlsAntioxidantieninLichtschutzmittelnvonInteresse!

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Stress induced responses ...Stresstriggersnoradrenalin,glucocorticoids,

...

2007

Cartoon:FriedrichMarks–MolekulareBiologiederHormone-UTB

EndokrinaktiveSubstanzeninSonnenschutzmitteln

Ardeystr.67●D-44139Dortmund●www.ifado.de

Danke für Ihr Interesse !

²  EndocrineActiveSubstance/EndocrineDisruptor•  Definitions;Concerns;•  ModesofAction;Challenges

²  EuropeanRegulatoryArena–diversetasks•  CriteriaforidentificationofanEndocrinedisruptor

²  SCCS(&others)onEAS/EDasCosmeticIngredients§  Safety evaluation: Hazard, Exposure and Risk assessment

§  UVfilter:Annex VII compounds

§  Parabens: safe levels defined, but ... (Science // other players )

Ausblick–Diskussion

Apologiesford-english