Skip to main content

Thank you for visiting 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.

Migration of cyclohexanone and 3,3,5-trimethylcyclohexanone from a neonatal enteral feeding system into human milk



Estimate the migration of volatile organic compounds (VOCs) which have been identified by the EPA as a public health concern, from the enteral feeding system into human milk.

Study design

Unfortified human milk samples were infused through an enteral feeding system with varying duration of infusion, incubator temperature, and pre-infusion tube priming. Purge & Trap analysis and GC/MS were used to identify the VOC profile of milk pre- and post-infusion.


Cyclohexanone and 3,3,5-trimethylcyclohexanone (3,3,5-TMC) accumulated significantly in milk samples post-infusion. Duration of infusion had a significant effect on VOC accumulation (p = 0.001). Accumulation patterns of cyclohexanone and 3,3,5-TMC differed significantly based on milk type (donor vs. mother’s own milk).


VOCs, migrate from plastic-based feeding equipment into human milk. Based on these findings, limiting the duration of feeding infusion would reduce VOC exposure derived from enteral feeding in the neonatal intensive care unit.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



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

Fig. 1
Fig. 2
Fig. 3


  1. United States Environmental Protection Agency. Volatile organic compounds’ impact on indoor air quality. EnviroAtlas. Accessed 13 Aug 2019.

  2. Bazyar J, Pourvakhshoori N, Khankeh H, Farrokhi M, Delshad V, Rajabi E. A comprehensive evaluation of the association between ambient air pollution and adverse health outcomes of major organ systems: a systematic review with a worldwide approach. Environ Sci Pollut Res Int. 2019;26(May):12648–61.

    Article  CAS  PubMed  Google Scholar 

  3. Otto D, Molhave L, Rose G, Hudnell HK, House D. Neurobehavioral and sensory irritant effects of controlled exposure to a complex mixture of volatile organic compounds. Neurotoxicol Teratol. 1990;12(Nov-Dec):649–52.

    Article  CAS  PubMed  Google Scholar 

  4. Tsai WT. An overview of health hazards of volatile organic compounds regulated as indoor air pollutants. Rev Environ Health. 2019;34(Mar):81–9.

    Article  CAS  PubMed  Google Scholar 

  5. Ran J, Qiu H, Sun S, Yang A, Tian L. Are ambient volatile organic compounds environmental stressors for heart failure? Environ Pollut. 2018;242(Nov):1810–6.

    Article  CAS  PubMed  Google Scholar 

  6. Chang M, Park H, Ha M, Hong Y, Lim Y, Kim Y. et al. The effect of prenatal TVOC exposure on birth and infantile weight: the mothers and children’s environmental health study. Pediatr Res. 2017;82(Sep):423–8.

    Article  CAS  PubMed  Google Scholar 

  7. Perera F, Hemminki K, Jedrychowski W, Whyatt R, Campbell U, Hsu Y, et al. In utero DNA damage from environmental pollution is associated with somatic gene mutation in newborns. Cancer Epidemiol Biomark Prev. 2002;11(10 Pt 1):1134–7.

    CAS  Google Scholar 

  8. Faustman EM. Mechanisms underlying children’s susceptibility to environmental toxicants. Environ Health Perspect. 2000;108:13–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Rumchev K, Spickett J, Bulsara M, Phillips M, Stick S. Association of domestic exposure to volatile organic compounds with asthma in young children. Thorax. 2004;59(Sep):746–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim J, Kim E MS, Oh I, Jung K, Han Y, Cheong H, et al. Symptoms of atopic dermatitis are influenced by outdoor air pollution. J Allergy Clin Immunol. 2013;132(Aug):495–e1.

    Article  CAS  PubMed  Google Scholar 

  11. Prazad P, Cortes DR, Puppala BL, Donovan R, Kumar S, Gulati A. Airborne concentrations of volatile organic compounds in neonatal incubators. J Perinatol. 2008;28:534–40.

    Article  CAS  PubMed  Google Scholar 

  12. Eppler M, Donovan R, Schweig L, Cortes DR, Prazad P, Gulati A, et al. Effect of phototherapy on airborne concentrations of volatile organic compounds found in neonatal incubators. J Neonatal Perinat Med. 2012;5:221–7.

    Article  Google Scholar 

  13. Ugarte UC, Prazad P, Puppala BL, Schweig L, Donovan R, Cortes DR, et al. Emission of volatile organic compounds from medical equipment inside neonatal incubators. J Perinatol. 2014;34:624–8.

    Article  Google Scholar 

  14. Ulsaker GA, Korsnes RM. Communication. Determination of cyclohexanone in intravenous solutions stored in PVC bags by gas chromatography. Analyst. 1977;102:882.

    Article  CAS  PubMed  Google Scholar 

  15. Snell RP. Gas chromatographic determination of cyclohexanone leached from hemodialysis tubing. J AOAC Int. 1993;75:1127–32.

    Article  Google Scholar 

  16. Snell RP. Capillary GC analysis of compounds leached into parenteral solutions packaged in plastic bags. J Chromatogr Sci. 1989;27:524–8.

    Article  CAS  PubMed  Google Scholar 

  17. U.S. EPA. Provisional peer-reviewed toxicity values for cyclohexanone. U.S. Environmental Protection Agency, Washington, DC, 2010.

  18. Gupta P, Lawrence W, Turner J, Autian J. Toxicological aspects of cyclohexanone. Toxicol Appl Pharm. 1979;49:525–33.

    Article  CAS  Google Scholar 

  19. Koeferl MT, Miller TR, Fisher JD, Martis L, Garvin PJ, Dorner JL. Influence of concentration and rate of intravenous administration on the toxicity of cyclohexanone in beagle dogs. Toxicol Appl Pharm. 1981;59:215–29.

    Article  CAS  Google Scholar 

  20. Lim CH, Lee YH, Kim YS, Choi HS, Seo DS. Assessment of cyclohexanone toxicity in inhalation-exposed F344 rats and B6C3F1 mice: applications in occupational health. Inhal Toxicol. 2018;30:247–54.

    Article  CAS  PubMed  Google Scholar 

  21. Thompson-Torgerson CS, Champion HC, Santhanam L, Harris ZL, Shoukas AA. Cyclohexanone contamination from extracorporeal circuits impairs cardiovascular function. Am J Physiol Heart Circ Physiol. 2009;296:H1926–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Falk O, Jacobsson S. Determination of cyclohexanone in aqueous solutions stored in PVC bags by isotope dilution gas chromatography—mass spectrometry. J Pharm Biomed Anal. 1989;7:1217–20.

    Article  CAS  PubMed  Google Scholar 

  23. Danielson JW. Capillary gas chromatographic determination of cyclohexanone and 2-ethyl-1-hexanol leached from solution administration sets. J Assoc Anal Chem. 1991;74:476–8.

    CAS  Google Scholar 

  24. Everett AD, Buckley JP, Ellis G, et al. Association of neurodevelopmental outcomes with environmental exposure to cyclohexanone during neonatal congenital cardiac operations: a secondary analysis of a randomized clinical trial. JAMA Netw Open 2020;3(May):e204070.

    Article  PubMed  PubMed Central  Google Scholar 

  25. El-Metawally D, Chain K, Stefanak MP, Alwis U, Blount BC, LaKind JS, et al. Urinary metabolites of volatile organic compounds of infants in the neonatal intensive care unit. Pediatr Res. 2018;83:1158–64.

    Article  Google Scholar 

  26. Mills GA, Walker V. Urinary excretion of cyclohexanediol, a metabolite of the solvent cyclohexanone, by infants in a special care unit. Clin Chem. 1990;36:870–4.

    Article  CAS  PubMed  Google Scholar 

  27. Kim S, Halden R, Buckley T. Volatile organic compounds in human milk: methods and measurements. Environ Sci Technol. 2007;41:1662–7.

    Article  CAS  PubMed  Google Scholar 

  28. Lehmann GM, LaKind JS, Davis MH, Hines EP, Marchitti SA, Alcala C, et al. Environmental chemicals in breast milk and formula: exposure and risk assessment implications. Environ Health Perspect 2018;126(Sep):96001.

    Article  CAS  PubMed  Google Scholar 

  29. Blount BC, McElprang DO, Chambers DM, Waterhouse MG, Squibb KS, Lakind JS. Methodology for collecting, storing, and analyzing human milk for volatile organic compounds. J Environ Monit. 2010;12(Jun):1265–73.

    Article  CAS  PubMed  Google Scholar 

  30. Cortes DR, Basu I, Sweet CW, Brice KA, Hoff RM, Hites RA. Temporal trends in gas-phase concentrations of chlorinated pesticides measured at the shores of the great lakes. Environ Sci Technol. 1998;32:1920–7.

    Article  CAS  Google Scholar 

  31. Bozzetti V, Tagliabue PE. Enteral nutrition for preterm infants: by bolus or continuous? An update. Pediatr Med Chir. 2017;39:159.

    PubMed  Google Scholar 

  32. Occupational Safety and Health Administration (OSHA). Regulations (Standards—29 CFR): TABLE Z-1 limits for air contaminants. Accessed 2 Feb 2004.

  33. Martis L, Tolhurst T, Koeferl MT, Miller TR, Darby TD. Disposition kinetics of cyclohexanone in beagle dogs. Toxicol Appl Pharm. 1980;55:545–53.

    Article  CAS  Google Scholar 

  34. OECD/SIDS. Screening information data set (SIDS) of OECD high production volume chemicals programme. 1994.

  35. CDC—NIOSH Pocket Guide to Chemical Hazards—Cyclohexanone. Centers for disease control and prevention. (2018). Accessed 17 Jul 2019.

  36. 3,3,5-trimethylcyclohexan-1-one—Registration Dossier. ECHA. (2019). Accessed 17 Jul 2019.

  37. Safety Data Sheet. Sigma-Aldrich. (2019). Accessed 15 Jul 2019.

  38. Meier P, Patel A, Esquerra-Zwiers A. Donor human milk update: evidence, mechanisms, and priorities for research and practice. J Pediatr. 2017;180(Jan):15–21.

    Article  PubMed  Google Scholar 

  39. Peila C, Moro GE, Bertino E, Cavallarin L, Giribaldi M, Giulani F, et al. The effect of holder pasteurization on nutrients and biologically-active components in donor human milk: a review. Nutrients. 2016;8(Aug):477.

    Article  PubMed Central  Google Scholar 

  40. Silvestre D, Miranda M, Muriach M, Almansa I, Jareno E, Romero FJ. Antioxidant capacity of human milk: effect of thermal conditions for the pasteurization. Acta Paediatr. 2008;97:1070–4.

    Article  CAS  PubMed  Google Scholar 

Download references


This research was supported by a grant from the Russell Institute for Research and Innovation. Thanks to Yi Li, MS for her guidance on statistical analysis and interpretation for this project and to Madeline Newman for assistance with background research for protocol development.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Preetha Prazad.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prazad, P., Donovan, R., Won, B. et al. Migration of cyclohexanone and 3,3,5-trimethylcyclohexanone from a neonatal enteral feeding system into human milk. J Perinatol 41, 1074–1082 (2021).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links