Mono-n-hexyl phthalate: exposure estimation and assessment of health risks based on levels found in human urine samples.
Benchmark dose modelling
Di-n-hexyl phthalate
Human biomonitoring data
Mono-n-hexyl phthalate
Reverse dosimetry
Tolerable daily intake
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
17 Aug 2024
17 Aug 2024
Historique:
received:
03
07
2024
accepted:
05
08
2024
medline:
17
8
2024
pubmed:
17
8
2024
entrez:
17
8
2024
Statut:
aheadofprint
Résumé
Mono-n-hexyl phthalate (MnHexP) is a primary metabolite of di-n-hexyl phthalate (DnHexP) and other mixed side-chain phthalates that was recently detected in urine samples from adults and children in Germany. DnHexP is classified as toxic for reproduction category 1B in Annex VI of Regulation (EC) 1272/2008 and listed in Annex XIV of the European chemical legislation REACH; thereby, its use requires an authorisation. Health-based guidance values for DnHexP are lacking and a full-scale risk assessment has not been carried out under REACH. The detection of MnHexP in urine samples raises questions about the sources of exposure and concerns of consumer safety. Here, we propose the calculation of a provisional oral tolerable daily intake value (TDI) of 63 µg/kg body weight/day for DnHexP and compare it to intake levels corresponding to levels of MnHexP found in urine. The resulting mean intake levels correspond to less than 0.2% of the TDI, and maximum levels to less than 5%. The TDI was derived by means of an approximate probabilistic analysis using the credible interval from benchmark dose modelling of published ex vivo data on reduced foetal testosterone production in rats. Thus, for the dose associated to a 20% reduction in testosterone production, a lower and upper credible interval of 14.9 and 30.0 mg/kg bw/day, respectively, was used. This is considered a conservative approach, since apical developmental endpoints (e.g. changed anogenital distance) were only observed at higher doses. In addition, we modelled various scenarios of the exposure to the precursor substance DnHexP from different consumer products, taking measured contamination levels into account, and estimated systemic exposure doses. Of the modelled scenarios including the application of sunscreen (as a lotion or pump spray), the use of lip balm, and the wearing of plastic sandals, and considering conservative assumptions, the use of DnHexP-contaminated sunscreen was highlighted as a major contributing factor. A hypothetical calculation using conservative assumptions for the latter resulted in a margin of safety in relation to the lower credible interval of 3267 and 1007 for adults and young children, respectively. Most importantly, it was found that only a fraction of the TDI is reached in all studied exposure scenarios. Thus, with regard to the reported DnHexP exposure, a health risk can be considered very unlikely.
Identifiants
pubmed: 39153032
doi: 10.1007/s00204-024-03835-x
pii: 10.1007/s00204-024-03835-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Akkbik M, Turksoy VA, Kocoglu S (2020) Simultaneous quantitative detection of 10 phthalates in PVC children’s toys by HPLC-PDA. Toxicol Mech Methods 30(1):33–38. https://doi.org/10.1080/15376516.2019.1650145
doi: 10.1080/15376516.2019.1650145
pubmed: 31364916
Al Qasmi NN, Al-Thaiban H, Helaleh MIH (2019) Indoor phthalates from household dust in Qatar: implications for non-dietary human exposure. Environ Sci Pollut Res Int 26(1):421–430. https://doi.org/10.1007/s11356-018-3604-8
doi: 10.1007/s11356-018-3604-8
pubmed: 30406583
Ali N, Rashid MI, Alhakamy NA, Alamri SH, Eqani S (2023) Profiling of phthalates, brominated, and organophosphate flame retardants in COVID-19 lockdown house dust; implication on the human health. Sci Total Environ 856(Pt 1):158779. https://doi.org/10.1016/j.scitotenv.2022.158779
doi: 10.1016/j.scitotenv.2022.158779
pubmed: 36116658
Anderson WA, Castle L, Scotter MJ, Massey RC, Springall C (2001) A biomarker approach to measuring human dietary exposure to certain phthalate diesters. Food Addit Contam 18(12):1068–1074. https://doi.org/10.1080/02652030110050113
doi: 10.1080/02652030110050113
pubmed: 11761117
Anderson WA, Castle L, Hird S, Jeffery J, Scotter MJ (2011) A twenty-volunteer study using deuterium labelling to determine the kinetics and fractional excretion of primary and secondary urinary metabolites of di-2-ethylhexylphthalate and di-iso-nonylphthalate. Food Chem Toxicol 49(9):2022–2029. https://doi.org/10.1016/j.fct.2011.05.013
doi: 10.1016/j.fct.2011.05.013
pubmed: 21609750
Aylward LL, Hays SM, Vezina A, Deveau M, St-Amand A, Nong A (2015) Biomonitoring equivalents for interpretation of urinary fluoride. Regul Toxicol Pharmacol 72(1):158–167. https://doi.org/10.1016/j.yrtph.2015.04.005
doi: 10.1016/j.yrtph.2015.04.005
pubmed: 25863192
Aylward LL, Hays SM, Zidek A (2017) Variation in urinary spot sample, 24 h samples, and longer-term average urinary concentrations of short-lived environmental chemicals: implications for exposure assessment and reverse dosimetry. J Expo Sci Environ Epidemiol 27(6):582–590. https://doi.org/10.1038/jes.2016.54
doi: 10.1038/jes.2016.54
pubmed: 27703149
Basaran B, Soylu GN, Yilmaz Civan M (2020) Concentration of phthalate esters in indoor and outdoor dust in Kocaeli, Turkey: implications for human exposure and risk. Environ Sci Pollut Res Int 27(2):1808–1824. https://doi.org/10.1007/s11356-019-06815-2
doi: 10.1007/s11356-019-06815-2
pubmed: 31758479
BfR (2023) Bisphenol A: BfR proposes health based guidance value, current exposure data are needed for a full risk assessment BfR Opinion. German Federal Institute for Risk Assessment, 018/2023 https://www.bfr.bund.de/cm/349/bisphenol-a-bfr-proposes-health-based-guidance-value-current-exposure-data-are-needed-for-a-full-risk-assessment.pdf
BfR (2024) MnHexP: Background information on the detection of the degradation product of a plasticizer in urine samples Communication. German Federal Institute for Risk Assessment, 04/2024. https://www.bfr.bund.de/cm/349/mnhexp-background-information-on-the-detection-of-the-degradation-product-of-a-plasticizer-in-urine-samples.pdf
CVUA Karlsruhe (2024) [Prohibited Plasticiser as Contamination in Sunscreen? Initial findings of an investigation]—in German. In. https://www.ua-bw.de/pub/beitrag.asp?subid=0&Thema_ID=4&ID=3940&Pdf=No&lang=DE Accessed 18.04.2024 2024
Demirtepe H, Melymuk L, Codling G et al (2021) Targeted and suspect screening of plasticizers in house dust to assess cumulative human exposure risk. Sci Total Environ 781:146667. https://doi.org/10.1016/j.scitotenv.2021.146667
doi: 10.1016/j.scitotenv.2021.146667
pubmed: 33812101
Dodson RE, Camann DE, Morello-Frosch R, Brody JG, Rudel RA (2015) Semivolatile organic compounds in homes: strategies for efficient and systematic exposure measurement based on empirical and theoretical factors. Environ Sci Technol 49(1):113–122. https://doi.org/10.1021/es502988r
doi: 10.1021/es502988r
pubmed: 25488487
ECHA (2013) Registry of SVHC intentions until outcome—Dihexyl phthalate. In. https://echa.europa.eu/registry-of-svhc-intentions/-/dislist/details/0b0236e180e4ab8c Accessed 2024-05-28
ECHA (2016) Annex XV Restriction Report. Proposal for a restriction—substance names: Four phthalates (DEHP, BBP, DBP, DIBP). ECHA. https://echa.europa.eu/documents/10162/2700f4f2-579a-1fbe-2c23-311706a3e958
ECHA (2020) Authorisation List - Dihexyl phthalate. In. https://echa.europa.eu/authorisation-list/-/dislist/details/0b0236e180912a44 Accessed 2024-05-28
EFSA (2019) Update of the risk assessment of di-butylphthalate (DBP), butyl-benzyl-phthalate (BBP), bis(2-ethylhexyl)phthalate (DEHP), di-isononylphthalate (DINP) and di-isodecylphthalate (DIDP) for use in food contact materials. EFSA J 17(12):e05838. https://doi.org/10.2903/j.efsa.2019.5838
doi: 10.2903/j.efsa.2019.5838
EFSA (2022) Guidance on the use of the benchmark dose approach in risk assessment. EFSA J 20(10):e07584. https://doi.org/10.2903/j.efsa.2022.7584
doi: 10.2903/j.efsa.2022.7584
EFSA (2024) Bayesian Benchmark Dose Modelling. In: EFSA. https://r4eu.efsa.europa.eu/app/bmdbayesian Accessed 2024-05-06
Elsisi AE, Carter DE, Sipes IG (1989) Dermal absorption of phthalate diesters in rats. Fundam Appl Toxicol 12(1):70–77. https://doi.org/10.1016/0272-0590(89)90063-8
doi: 10.1016/0272-0590(89)90063-8
pubmed: 2925020
Fabjan E, Hulzebos E, Mennes W, Piersma AH (2006) A category approach for reproductive effects of phthalates. Crit Rev Toxicol 36(9):695–726. https://doi.org/10.1080/10408440600894914
doi: 10.1080/10408440600894914
pubmed: 17050082
Ficheux AS, Dornic N, Bernard A, Chevillotte G, Roudot AC (2016) Probabilistic assessment of exposure to cosmetic products by French children aged 0–3 years. Food Chem Toxicol 94:85–92. https://doi.org/10.1016/j.fct.2016.05.020
doi: 10.1016/j.fct.2016.05.020
pubmed: 27255804
Fisher M, Arbuckle TE, Mallick R et al (2015) Bisphenol A and phthalate metabolite urinary concentrations: daily and across pregnancy variability. J Expo Sci Environ Epidemiol 25(3):231–239. https://doi.org/10.1038/jes.2014.65
doi: 10.1038/jes.2014.65
pubmed: 25248937
Frederiksen H, Aksglaede L, Sorensen K, Skakkebaek NE, Juul A, Andersson AM (2011) Urinary excretion of phthalate metabolites in 129 healthy Danish children and adolescents: estimation of daily phthalate intake. Environ Res 111(5):656–663. https://doi.org/10.1016/j.envres.2011.03.005
doi: 10.1016/j.envres.2011.03.005
pubmed: 21429484
Frederiksen H, Kranich SK, Jorgensen N, Taboureau O, Petersen JH, Andersson AM (2013) Temporal variability in urinary phthalate metabolite excretion based on spot, morning, and 24-h urine samples: considerations for epidemiological studies. Environ Sci Technol 47(2):958–967. https://doi.org/10.1021/es303640b
doi: 10.1021/es303640b
pubmed: 23234290
Furr JR, Lambright CS, Wilson VS, Foster PM, Gray LE Jr (2014) A short-term in vivo screen using fetal testosterone production, a key event in the phthalate adverse outcome pathway, to predict disruption of sexual differentiation. Toxicol Sci 140(2):403–424. https://doi.org/10.1093/toxsci/kfu081
doi: 10.1093/toxsci/kfu081
pubmed: 24798384
pmcid: 4471440
Guo Y, Kannan K (2011) Comparative assessment of human exposure to phthalate esters from house dust in China and the United States. Environ Sci Technol 45(8):3788–3794. https://doi.org/10.1021/es2002106
doi: 10.1021/es2002106
pubmed: 21434628
HBM Commission (2024) [HBM-I value derivation for the di-n-hexyl phthalate metabolite mono-n-hexyl phthalate in the urine of adults and children] - in German. UBA. https://www.umweltbundesamt.de/sites/default/files/medien/11901/dokumente/240325_kurz-stellungnahme_hbm-k_fin.pdf
HBM4EU (2022) Suggested list of biomarkers, matrices and analytical methods for the 1st prioritisation round of substances. https://www.hbm4eu.eu/?mdocs-file=2662
Kessler W, Numtip W, Volkel W et al (2012) Kinetics of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate in blood and of DEHP metabolites in urine of male volunteers after single ingestion of ring-deuterated DEHP. Toxicol Appl Pharmacol 264(2):284–291. https://doi.org/10.1016/j.taap.2012.08.009
doi: 10.1016/j.taap.2012.08.009
pubmed: 22963843
Koch HM, Bolt HM, Angerer J (2004) Di(2-ethylhexyl)phthalate (DEHP) metabolites in human urine and serum after a single oral dose of deuterium-labelled DEHP. Arch Toxicol 78(3):123–130. https://doi.org/10.1007/s00204-003-0522-3
doi: 10.1007/s00204-003-0522-3
pubmed: 14576974
Koch HM, Bolt HM, Preuss R, Angerer J (2005) New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP. Arch Toxicol 79(7):367–376. https://doi.org/10.1007/s00204-004-0642-4
doi: 10.1007/s00204-004-0642-4
pubmed: 15700144
Koch HM, Becker K, Wittassek M, Seiwert M, Angerer J, Kolossa-Gehring M (2007) Di-n-butylphthalate and butylbenzylphthalate—urinary metabolite levels and estimated daily intakes: pilot study for the German Environmental Survey on children. J Expo Sci Environ Epidemiol 17(4):378–387. https://doi.org/10.1038/sj.jes.7500526
doi: 10.1038/sj.jes.7500526
pubmed: 17006438
Koch HM, Christensen KL, Harth V, Lorber M, Bruning T (2012) Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses. Arch Toxicol 86(12):1829–1839. https://doi.org/10.1007/s00204-012-0908-1
doi: 10.1007/s00204-012-0908-1
pubmed: 22820759
Koch HM, Ruther M, Schutze A et al (2017) Phthalate metabolites in 24-h urine samples of the German Environmental Specimen Bank (ESB) from 1988 to 2015 and a comparison with US NHANES data from 1999 to 2012. Int J Hyg Environ Health 220(2 Pt A):130–141. https://doi.org/10.1016/j.ijheh.2016.11.003
doi: 10.1016/j.ijheh.2016.11.003
pubmed: 27863804
Krais AM, Andersen C, Eriksson AC et al (2018) Excretion of urinary metabolites of the phthalate esters DEP and DEHP in 16 volunteers after inhalation and dermal exposure. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph15112514
doi: 10.3390/ijerph15112514
pubmed: 30423997
pmcid: 6266104
Kremer C, Oluwafemi O, Shkedy Z et al (2024) Bayesian benchmark dose modelling WEB app. In: Zenodo. https://zenodo.org/records/10523648 . Accessed 2024-05-06
Kubwabo C, Rasmussen PE, Fan X et al (2013) Analysis of selected phthalates in Canadian indoor dust collected using household vacuum and standardized sampling techniques. Indoor Air 23(6):506–514. https://doi.org/10.1111/ina.12048
doi: 10.1111/ina.12048
pubmed: 23621316
Lange R, Apel P, Rousselle C et al (2021) The European Human Biomonitoring Initiative (HBM4EU): human biomonitoring guidance values for selected phthalates and a substitute plasticizer. Int J Hyg Environ Health 234:113722. https://doi.org/10.1016/j.ijheh.2021.113722
doi: 10.1016/j.ijheh.2021.113722
pubmed: 33711757
LANUV (2021) Determination of pollutants and pollutant metabolites in the urine of 2- to 6-year-old children from North Rhine-Westphalia, report on the 3rd cross-section (2017/18), module 1 (plasticisers)—in German. Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen. https://www.lanuv.nrw.de/fileadmin/lanuv/gesundheit/pdf/2021/1_Modul_HBM_201718_final.pdf
LANUV (2022) Determination of pollutants and pollutant metabolites in the urine of 2- to 6-year-old children from North Rhine-Westphalia, report on the 4th cross-section (2020/21), module 1 (plasticisers)—in German. Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen. https://www.lanuv.nrw.de/fileadmin/lanuv/gesundheit/pdf/2022/Modul_1_HBM_202021_final.pdf
LANUV (2024) Determination of pollutants and pollutant metabolites in the urine of 2- to 6-year-old children from North Rhine-Westphalia—LANUV follow-up study on the plasticiser metabolite mono-n-hexyl phthalate (MnHexP)]—in German. Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen, V.01/2024. https://www.lanuv.nrw.de/fileadmin/lanuv/gesundheit/pdf/2024/2024-01_Nachuntersuchung_DnHexP.pdf
Net S, Sempere R, Delmont A, Paluselli A, Ouddane B (2015) Occurrence, fate, behavior and ecotoxicological state of phthalates in different environmental matrices. Environ Sci Technol 49(7):4019–4035. https://doi.org/10.1021/es505233b
doi: 10.1021/es505233b
pubmed: 25730609
Pakalin S, Aschberger K, Cosgrove O et al (2008) European Union Risk Assessment Report—bis (2-ethylhexyl) phthalate (DEHP). Luxembourg (Luxembourg), EUR 23384 EN. https://publications.jrc.ec.europa.eu/repository/bitstream/JRC45705/dehpreport042.pdf
Pfaff K, Kappenstein O, Ebner I, Würtz A (2012) Phthalate exposure of the population in Germany: Exposure-relevant sources, uptake pathways and toxicokinetics using the example of DEHP and DINP - Volume II: Supplementary measurements of DEHP, DINP and DiNCH in food and migration measurements in consumer products—in German. In: Conrad A, Wintermeyer D (eds). German Federal Environmental Agency, Dessau-Roßlau, 03/2012. https://www.umweltbundesamt.de/sites/default/files/medien/378/publikationen/umwelt_und_gesundheit_03_2012_conrad_phthalatbelastung_bevoelkerung_band2_a.pdf
Saillenfait AM, Roudot AC, Gallissot F, Sabate JP, Chagnon MC (2011) Developmental toxic potential of di-n-propyl phthalate administered orally to rats. J Appl Toxicol 31(1):36–44. https://doi.org/10.1002/jat.1565
doi: 10.1002/jat.1565
pubmed: 20652869
Saillenfait AM, Sabate JP, Robert A et al (2013) Dose-dependent alterations in gene expression and testosterone production in fetal rat testis after exposure to di-n-hexyl phthalate. J Appl Toxicol 33(9):1027–1035. https://doi.org/10.1002/jat.2896
doi: 10.1002/jat.2896
pubmed: 23754470
SCCP (2007) Opinion on phthalates in cosmetic products. SCCP/1016/06. https://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_106.pdf
SCCS (2021) Opinion on homosalate. SCCS/1622/20. https://health.ec.europa.eu/document/download/ddf0b68f-5c47-4ace-a87f-0a0e42ebd4a9_en?filename=sccs_o_244.pdf
SCCS (2023) The SCCS Notes of Guidance for the testing of cosmetic ingredients and their safety evaluation, 12th revision. In: (SCCS) SCoCS (ed). 20231222 edn. European Union, SCCS/1647/22. https://health.ec.europa.eu/document/download/32a999f7-d820-496a-b659-d8c296cc99c1_en?filename=sccs_o_273_final.pdf
Slob W (2017) A general theory of effect size, and its consequences for defining the benchmark response (BMR) for continuous endpoints. Crit Rev Toxicol 47(4):342–351. https://doi.org/10.1080/10408444.2016.1241756
doi: 10.1080/10408444.2016.1241756
pubmed: 27805866
Steiling W, Bascompta M, Carthew P et al (2014) Principle considerations for the risk assessment of sprayed consumer products. Toxicol Lett 227(1):41–49. https://doi.org/10.1016/j.toxlet.2014.03.005
doi: 10.1016/j.toxlet.2014.03.005
pubmed: 24657525
Tang Z, Chai M, Wang Y, Cheng J (2020) Phthalates in preschool children’s clothing manufactured in seven Asian countries: occurrence, profiles and potential health risks. J Hazard Mater 387:121681. https://doi.org/10.1016/j.jhazmat.2019.121681
doi: 10.1016/j.jhazmat.2019.121681
pubmed: 31757725
UBA (2011) Substance monograph for phthalates - New and updated reference and oxidised monoester metabolites in urine of children-and adults. Opinion of the Commission “Human-Biomonitoring” by the Federal Environment Agency—in German. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 54(6):770–785. https://doi.org/10.1007/s00103-011-1278-1
UBA (2024a) Assessment value set for plasticisers in urine—HBM Commission at the German Environment Agency publishes statement German Federal Environmental Agency, Dessau-Roßlau. https://www.umweltbundesamt.de/en/press/pressinformation/assessment-value-set-for-plasticisers-in-urine
UBA (2024b) German Environmental Survey, GerES VI (2023–2024). In. https://www.umweltbundesamt.de/en/topics/health/assessing-environmentally-related-health-risks/german-environmental-survey-geres/german-environmental-survey-geres-vi-2023-2024 . Accessed 18.04.2024
Verlinden W, Varewyck M, Verbeke T (2024) Web application for bayesian benchmark dose modelling. EFSA Support Public 21(1):8580E. https://doi.org/10.2903/sp.efsa.2024.EN-8580
doi: 10.2903/sp.efsa.2024.EN-8580
Vilmand M, Beck IH, Bilenberg N et al (2023) Prenatal and current phthalate exposure and cognitive development in 7-year-old children from the Odense child cohort. Neurotoxicol Teratol 96:107161. https://doi.org/10.1016/j.ntt.2023.107161
doi: 10.1016/j.ntt.2023.107161
pubmed: 36690047
WHO (2018) Guidance document on evaluating and expressing uncertainty in hazard characterization, 2nd edn. World Health Organization, Geneva. https://iris.who.int/handle/10665/259858