Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Di-n-butylphthalate and butylbenzylphthalate — urinary metabolite levels and estimated daily intakes: pilot study for the German Environmental Survey on children

Journal of Exposure Science & Environmental Epidemiology volume 17, pages 378–387 (2007)Cite this article

Abstract

We analysed urine samples from the 2001/2002 pilot study of the German Environmental Survey on Children (GerES IV) for the concentrations of the di-n-butylphthalate (DnBP) metabolite mono-n-butylphthalate (MnBP) and the butlybenzylphthalate (BBzP) metabolite mono-benzyl-phthalate (MBzP). The study population consisted of 239 children (106 boys, 133 girls) aged between 2 and 14 years (median 8.5 years). We applied two calculation models to estimate the daily intake for the two parent phthalates from metabolite excretion. One was based on the creatinine-related metabolite concentrations; the other was based on the volume-related metabolite concentrations. Median urinary metabolite concentrations were 174 μg/l (136 μg/g creatinine) for MnBP and 19.7 μg/l (15.3 μg/g creatinine) for MBzP. Such levels have been determined in German children before. Compared to the USA, German median MnBP levels were about 3–10 times higher, whereas MBzP levels were in the same range. Median daily intakes calculated with the creatinine-based model were 4.07 (range: 0.66–76.4; 95th percentile: 14.9) μg/kg body weight (bw)/day for DnBP and 0.42 (range: 0.06–13.9; 95th percentile: 2.57) μg/kg bw/day for BBzP. Daily intakes calculated with the volume-based model were approximately two times higher with a median of 7.61 (range: 0.91–110; 95th percentile: 30.5) μg/kg bw/day for DnBP and a median of 0.77 (range: 0.05–31.3; 95th percentile: 4.48) μg/kg bw/day for BBzP. Using the creatinine model, 28 (11.7%) of the 239 children exceeded the TDI for DnBP of 10 μg/kg bw/day defined by the European Union. Employing the volume model, 89 (37.2%) children exceeded the TDI. For BBzP, no preventive limit values (TDI or RfD) were exceeded. For both phthalates and independent of the model, we found increasing daily intakes with decreasing age. Between 25% (creatinine model) and 50% (volume model) of the 2–4-year old children had daily intakes for DnBP above the TDI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  • Adibi J.J., Perera F.P., Jedrychowski W., Camann D.E., Barr D., Jacek R., and Whyatt R.M. Prenatal exposures to phthalates among women in New York City and Krakow, Poland. Environ Health Perspect 2003: 111(14): 1719–1722.

    Article  CAS  Google Scholar 

  • Anderson W.A., Castle L., Scotter M.J., Massey R.C., and Springall C. A biomarker approach to measuring human dietary exposure to certain phthalate diesters. Food Addit Contam 2001: 18(12): 1068–1074.

    Article  CAS  Google Scholar 

  • Angerer J., and Weiss T., (Eds.). Biological Monitoring: Prospects in Occupational and Environmental Medicine. Wiley-VCH, Weinheim, Germany, 2002.

    Google Scholar 

  • Barr D.B., Wilder L.C., Caudill S.P., Gonzalez A.J., Needham L.L., and Pirkle J.L. Urinary creatinine concentrations in the US population: implications for urinary biologic monitoring measurements. Environ Health Perspect 2005: 113(2): 192–200.

    Article  CAS  Google Scholar 

  • Becker K., Seiwert M., Angerer A., Heger W., Koch H.M., Nagorka R., Roßkamp E., Schlüter C., Seifert B., and Ullrich D. DEHP metabolites in urine of children and DEHP in house dust. Int J Hyg Environ Health 2004: 207: 409–417.

    Article  CAS  Google Scholar 

  • Blount B.C., Silva M.J., Caudill S.P., Needham L.L., Pirkle J.L., Sampson E.J., Lucier G.W., Jackson R.J., and Brock J.W. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect 2000: 108(10): 979–982.

    Article  CAS  Google Scholar 

  • Brock J.W., Caudill S.P., Silva M.J., Needham L.L., and Hilborn E.D. Phthalate monoesters levels in the urine of young children. Bull Environ Contam Toxicol 2002: 68(3): 309–314.

    Article  CAS  Google Scholar 

  • Carruthers C.M., and Foster P.M. Critical window of male reproductive tract development in rats following gestational exposure to di-n-butyl phthalate. Birth Defects Res B Dev Reprod Toxicol 2005: 74(3): 277–285.

    Article  CAS  Google Scholar 

  • CDC (Centers for Disease Control and Prevention). Third National Report on Human Exposure to Environmental Chemicals – July 2005, Centers for Disease Control and Prevention; National Center for Environmental Health, Division of Laboratory Sciences, Atlanta, GA. (http://www.cdc.gov/exposurereport).

  • Clark K., Cousins I., and MacKay D. Assessment of critical exposure pathways. In: Staples (Ed.). The Handbook of Environmental Chemistry, 3Q: Phthalate Esters. Springer, New York, 2003 pp. 227–262.

    Google Scholar 

  • David R.M. Exposure to phthalate esters. Environ Health Perspect 2000: 108: A440.

    Article  CAS  Google Scholar 

  • Directive 2003/36/EC. Directive 2003/36/EC of the European Parliament and of the Council of 26 May 2003 amending, for the 25th time, Council Directive 76/769/EEC on the approximation of the laws, regulations and administrative provisions of the Member States relating to restrictions on the marketing and use of certain dangerous substances and preparations (substances classified as carcinogens, mutagens or substances toxic to reproduction — c/m/r). Official Journal L, 156, 25/6/2003 P. 0026–0030.

  • Directive 2004/93/EC. Directive 2004/93/EC of the European Parliament and of the Council of 21 September 2004 amending Council Directive 76/768/EEC for the purpose of adapting its Annexes II and III to technical progress. Official Journal L, 300, 25/9/2004 P. 0013–0041.

  • Directive 2005/84/EC. Directive 2005/84/EC of the European Parliament and of the Council of 14 December 2005 amending for the 22nd time Council Directive 76/769/EEC on the approximation of the laws, regulations and administrative provisions of the Member States relating to restrictions on the marketing and use of certain dangerous substances and preparations (phthalates in toys and childcare articles). Official Journal L, 344, 27/12/2005 P. 0040–0043.

  • ECB (European Commission — Joint Research Centre — Institute for Health and Consumer Protection — European Chemicals Bureau (ECB)). European Union Risk Assessment Report — Dibutyl Phthalate. Series: 1st Priority List, Volume: 29, EUR 19840 EN (with addendum 2004a). Available: http://ecb.jrc.it[accessed 09 February 2006].

  • ECB (European Commission — Joint Research Centre — Institute for Health and Consumer Protection — European Chemicals Bureau (ECB)). European Union Risk Assessment Report — Draft RAR on: Benzyl butyl phthalate — R318 0403 hh (March 2004b). Available: http://ecb.jrc.it[accessed 09 February 2006].

  • EFSA (European food Safety Authority). Opinion of the scientific panel on food additives, flavourings, processing aids and material in contact with food (AFC) on a request from the commission related to di-butylphthalate (DBP) for use in food contact materials — question No EFSA-Q-2003-192. EFSA J 2005a: 242: 1–17 Available: http://www.efsa.eu.int/science/afc/catindex_en.html.

  • EFSA (European food Safety Authority). Opinion of the scientific panel on food additives, flavourings, processing aids and materials in contact with food (AFC) on a request from the commission related to butylbenzylphthalate (BBP) for use in food contact materials — question No EFSA-Q-2003-190. EFSA J 2005b: 241: 1–14 Available: http://www.efsa.eu.int/science/afc/catindex_en.html.

  • EPA (US Environmental Protection Agency). Integrated Risk Information System (IRIS). Dibutyl phthalate (CASRN 84-74-2), National Center for Environmental Assessment, Office of Research and Development, Washington, DC, USA, 1990 Available: http://www.epa.gov/iris/[accessed 09 February 2006].

  • EPA (US Environmental Protection Agency). Integrated Risk Information System (IRIS). Butyl benzyl phthalate (CASRN 85-68-7), National Center for Environmental Assessment, Office of Research and Development, Washington, DC, USA, 1993 Available: http://www.epa.gov/iris/[accessed 09 February 2006].

  • FDA (US Food and Drug Administration). Inactive Ingredient Search for Approved Drug Products. US Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD. Database last updated: February 2, 2006 Available: http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm[accessed 09 February 2006].

  • Fisher J.S. Are all EDC effects mediated via steroid hormone receptors? Toxicology 2004: 205(1–2): 33–41.

    Article  CAS  Google Scholar 

  • Foster P.M. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. Int J Androl 2006: 29(1): 140–147.

    Article  CAS  Google Scholar 

  • Geigy (Ciba-Geigy A.G.) Wissenschaftliche Tabellen Geigy. Teilband Körperflüssigkeiten, 8. auflage, Basel, 1977.

  • Gray Jr L.E., Ostby J., Furr J., Price M., Veeramachaneni D.N., and Parks L. Perinatal exposure to the phthalates DEHP BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male Rat. Toxicol Sci 2000: 58: 350–365.

    Article  CAS  Google Scholar 

  • Gray Jr L.E., Wilson V.S., Stoker T., Lambright C., Furr J., Noriega N., Howdeshell K., Ankley G.T., and Guillette L. Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals. Int J Androl 2006: 29(1): 96–104.

    Article  CAS  Google Scholar 

  • Greene M.G. The Harriet Lane Handbook. A Manual for Pediatric House Officers. Mosby Year Book Inc., Hyattsville, MD, 1991.

    Google Scholar 

  • Harper H.A., Rodwell V.W., and Mayes P.A. Review of Physiological Chemistry. Lange Medical Publications, Los Altos, 1977.

    Google Scholar 

  • Hauser R., Duty S., Godfrey-Bailey L., and Calafat A.M. Medications as a source of human exposure to phthalates. Environ Health Perspect 2004: 112(6): 751–753.

    Article  Google Scholar 

  • Hotchkiss A.K., Parks-Saldutti L.G., Ostby J.S., Lambright C., Furr J., Vandenbergh J.G., and Gray Jr L.E. A mixture of the ‘antiandrogens’ linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. Biol Reproduct 2004: 71: 1852–1861.

    Article  CAS  Google Scholar 

  • Kavlock R., Barr D., Boekelheide K., Breslin W., Breysse P., Chapin R., Gaido K., Hodgsonh E., Marcus M., Shea K., and Williams P. NTP-CERHR expert panel update on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate. Reprod Toxicol, (in press, corrected proof, available online 21 June 2006, doi:10.1016/j.reprotox.2006.04.007).

  • Kavlock R., Boekelheide K., Chapin R., Cunningham M., Faustman E., Foster P., Golub M., Henderson R., Hinberg I., Little R., Seed J., Shea K., Tabacova S., Tyl R., Williams P., and Zacharewski T. NTP Center for the evaluation of risks to human reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-n-butyl phthalate. Reprod Toxicol 2002a: 16(5): 489–527.

    Article  CAS  Google Scholar 

  • Kavlock R., Boekelheide K., Chapin R., Cunningham M., Faustman E., Foster P., Golub M., Henderson R., Hinberg I., Little R., Seed J., Shea K., Tabacova S., Tyl R., Williams P., and Zacharewski T. NTP Center for the evaluation of risks to human reproduction: phthalates expert panel report on the reproductive and developmental toxicity of butyl benzyl phthalate. Reprod Toxicol 2002b: 16(5): 453–487.

    Article  CAS  Google Scholar 

  • Koch H.M., Drexler H., and Angerer J. An estimation of the daily intake of di(2-ethylhexyl)phthalate (dehp) and other phthalates in the general population. Int J Hyg Environ Health 2003a: 206(2): 77–83.

    Article  CAS  Google Scholar 

  • Koch H.M., Drexler H., and Angerer J. Internal exposure of nursery-school children and their parents and teachers to di(2-ethylhexyl)phthalate (DEHP). Int J Hyg Environ Health 2004: 207(1): 15–22.

    Article  CAS  Google Scholar 

  • Koch H.M., Gonzalez-Reche L.M., and Angerer J. On-line cleanup by multidimensional LC-ESI-MS/MS for high throughput quantification of primary and secondary phthalate metabolites in human urine. J Chromatogr B Analyt Technol Biomed Life Sci 2003b: 784: 169–182.

    Article  CAS  Google Scholar 

  • Koch H.M., Müller J., Drexler H., and Angerer J. Dibutylphthalat (DBP) in Arzneimitteln: ein bisher unterschätztes Risiko für Schwangere und Kleinkinder? [Dibutylphthalate (DBP) in medications: are pregnant women and infants at risk?]. Umweltmed Forsch Prax 2005a: 10(2): 144–146.

    Google Scholar 

  • Koch H.M., Preuss R., and Angerer J. Di(2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure — an update and latest results. Int J Androl 2006: 29(1): 155–165.

    Article  CAS  Google Scholar 

  • Koch H.M., Preuss R., Drexler H., and Angerer J. Exposure of nursery school children and their parents and teachers to di-n-butylphthalate and butylbenzylphthalate. Int Arch Occup Environ Health 2005b: 78(3): 223–229.

    Article  CAS  Google Scholar 

  • Koch H.M., Rossbach B., Drexler H., and Angerer J. Internal exposure of the general population to DEHP and other phthalates — determination of secondary and primary phthalate monoester metabolites in urine. Environ Res. 2003c: 93(2): 177–185.

    Article  CAS  Google Scholar 

  • Kohn M.C., Parham F., Masten S.A., Portier C.J., Shelby M.D., Brock J.W., and Needham L.L. Human exposure estimates for phthalates. Environ Health Perspect 2000: 108: A440–A442.

    Article  CAS  Google Scholar 

  • Lee K.Y., Shibutani M., Takagi H., Kato N., Shu T., Unemaya C., and Hirose M. Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation. Toxicology 2004: 203: 221–238.

    Article  CAS  Google Scholar 

  • McIntyre B.S., Barlow N.J., and Foster P.M. Male rats exposed to linuron in utero exhibit permanent changes in anogenital distance, nipple retention, and epididymal malformations that result in subsequent testicular atrophy. Toxicol Sci 2002: 65: 62–70.

    Article  CAS  Google Scholar 

  • Meek M.E., and Chan P.K. Bis(2-ethylhexyl)phthalate: evaluation of risks to health from environmental exposure in Canada. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 1994: 12: 179–194.

    Article  Google Scholar 

  • Mylchreest E., Wallace D.G., Cattley R.C., and Foster P.M. Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to di(n-butyl) phthalate during late gestation. Toxicol Sci 2000: 55(1): 143–151.

    Article  CAS  Google Scholar 

  • Nagao T., Ohta R., Marumo H., Shindo T., Yoshimura S., and Ono H. Effect of butyl benzyl phthalate in Sprague–Dawley rats after gavage administration: a two-generation reproductive study. Reprod Toxicol 2000: 14(6): 513–532.

    Article  CAS  Google Scholar 

  • NTP (National Toxicology Program). Twenty-six week subchronic study and modified mating trial in F344 rats. Butyl benzyl phthalate. Final Report. 1985. Project No. 12307-02, -03. Hazelton Laboratories America, Inc., unpublished study.

  • Preuss R., Koch H.M., and Angerer J. Biological monitoring of the major metabolites of di-(2-ethylhexyl)phthalate (DEHP) in human urine using column-switching liquid chromatography — tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2005: 816(1–2): 269–280.

    Article  CAS  Google Scholar 

  • Remer T., Neubert A., and Maser-Gluth C. Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. Am J Clin Nutr 2002: 75(3): 561–569.

    Article  CAS  Google Scholar 

  • Sharpe R.M., and Irvine D.S. How strong is the evidence of a link between environmental chemicals and adverse effects on human reproductive health? BMJ 2004: 328(7437): 447–451.

    Article  CAS  Google Scholar 

  • Shelby M.D. NTP center for the evaluation of risks to human reproduction phthalates expert panel reports. Reprod Toxicol 2002: 16(5): 451.

    Article  CAS  Google Scholar 

  • Silva M.J., Barr D.B., Reidy J.A., Malek N.A., Hodge C.C., and Caudill S.P., et al. Urinary levels of seven phthalate metabolites in the US population from the National Health and Nutrition Examination Survey (NHANES) 1999–2000. Environ Health Perspect 2004: 112(3): 331–338.

    Article  CAS  Google Scholar 

  • Silva M.J., Reidy J.A., Preau Jr J.L., Needham L.L., and Calafat A.M. Oxidative metabolites of di-iso-nonyl phthalate as biomarkers for human exposure assessment. Environ Health Perspect 2006: 114(8): 1158–1161.

    Article  CAS  Google Scholar 

  • Skakkebaek N.E., Rajpert-De Meyts E., and Main K.M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum. Reprod 2001: 16: 972–978.

    Article  CAS  Google Scholar 

  • Smith C.C. Toxicity of butyl sterate, dibutyl sebacate, dibutyl phthalate and methoxyethyl oleate. Arch Hyg Occup Med 1953: 7: 310–318.

    CAS  Google Scholar 

  • Tyl R.W., Myers C.B., Marr M.C., Fail P.A., Seely J.C., Brine D.R., Barter R.A., and Butala J.H. Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats. Reprod Toxicol 2004: 18(2): 241–264.

    Article  CAS  Google Scholar 

  • UBA (Federal Environment Agency). German Environmental Survey for Children (GerES IV). Brief description of the project, Federal Environment Agency, Berlin, 2005 (http://www.umweltbundesamt.de/survey-e/us03/uprog.htm).

  • Wilson V.S., Lambright C., Furr J., Ostby J., Wood C., Held G., and Gray Jr L.E. Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis. Toxicol Lett 2004: 146(3): 207–215.

    Article  CAS  Google Scholar 

  • Wine R.N., Li L.H., Barnes L.H., Gulati D.K., and Chapin R.E. Reproductive toxicity of di-n-butylphthalate in a continuous breeding protocol in Sprague–Dawley rats. Environ Health Perspect 1997: 105(1): 102–107.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Parts of the study have been financially supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) (DFG No.: AN 107/16-4). We thank the German Federal Environment Agency, which provided the urine samples from children of the 2001/2002 pilot study that preceded the German Environmental Survey on children (GerES IV).

Author information

Authors and Affiliations

  1. Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, Erlangen, Germany

    Holger M Koch, Matthias Wittassek & Jürgen Angerer

  2. Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin (BGFA), Institut der Ruhr-Universität Bochum, Bochum, Germany

    Holger M Koch

  3. Umweltbundesamt (Federal Environment Agency), Berlin, Germany

    Kerstin Becker, Margarete Seiwert & Marike Kolossa-Gehring

Authors
  1. Holger M Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kerstin Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthias Wittassek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margarete Seiwert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jürgen Angerer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marike Kolossa-Gehring
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Holger M Koch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koch, H., Becker, K., Wittassek, M. et al. 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, 378–387 (2007). https://doi.org/10.1038/sj.jes.7500526

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.jes.7500526

Keywords

This article is cited by

Search

Advanced search

Quick links