Diisobutyl phthalate (DIBP) is a phthalate ester having the structural formula C6H4(COOCH2CH(CH3)2)2. It is formed by the esterification of isobutanol and phthalic anhydride. This and other phthalates are used as plasticizers due to their flexibility and durability. They are found in many industrial and personal products, such as lacquers, nail polish and cosmetics. DIBP can be absorbed via oral ingestion and dermal exposition. When it comes to excretion, DIBP is first converted into the hydrolytic monoester monoisobutyl phthalate (MIBP). The primary excretory route is urine, with biliary excretion being noted in minor amounts. DIBP has lower density and freezing point than the related compound dibutyl phthalate (DBP).
In 1836 French chemist Auguste Laurent oxidized naphthalene with chromic acid and created phthalic anhydride, of which phthalates are derived.Phthalates, including DIBP, were first introduced in the 1920s to make plastics more flexible, transparent and long-lived. They increased their popularity in 1931 when polyvinylchloride (PVC) became commercially available. Due to the increase in human exposition to phthalates, in 1999 the European Union restricted the use of some of them in children’s toys.
December 14, 2005
The European Union restricted phthalates from several children’s toys.
It is used as an plasticizer additive in a range of plastic and rubber materials. It has low volatility, which makes it ideal for use in products that require long-lasting flexibility, e.g. automotive parts, wire and cable insulation, and flooring. It is dense and water-insoluble.
DIBP has been found to be relatively non-toxic, but high levels of exposure to the compound may cause irritation to the eyes, skin and respiratory tract. However, in recent years, concerns have been raised about the potential health risks of exposure to phthalates, including DIBP. Therefore, several countries have restricted or even banned the use of certain phthalates in products. DIBP has been detected in various environmental matrices, such as air, water, and sediment. DIBP is known to bioaccumulate in certain aquatic species
Sulfuric acid catalyzed reaction of isobutanol and phthalic anhydride to form diisobutyl phthalate
Sulfonated graphene is a heterogeneous catalyst that has several advantages over traditional liquid acids like sulfuric acid. Sulfonated graphene can be easily separated from the reaction mixture by filtration and can be reused multiple times without reduction in activity. Furthermore, sulfonated graphene is environmentally friendly, as it does not produce hazardous waste materials that are typically generated during the use of traditional liquid acid catalysts. This method has a 95% yield.
Diisobutyl phthalate is clear, colourless, oily liquid form with a mild odor. It is insoluble in water but soluble in many organic solvents.
DIBP can be sold as a pure substance or as a component of mixtures with other phthalate plasticizers or chemicals. Examples are dioctyl phthalate (DOP), diisononyl-phthalate (DINP), or bis(2-ethylhexyl) phthalate (DEHP). It may be used as a component in formulations of several products including adhesives, paints, coatings and lubricants. DIBP also may be present in consumer products such as toys, vinyl flooring, food packaging, and as a plasticizer or as a component of plastic formulations. In many of these products DIBP is now prohibited to be used in formulations according to REACH.
DIBP can undergo various reactions that may impact the environment. Examples include:
Hydrolysis: Hydrolyzation of DIBP can be done by enzymes, bacteria, and other microorganisms in the environment to form phthalic acid and isobutyl alcohol. This can lead to the breakdown and the eventual degradation of DIBP in the soil and water supply
The metabolism of DiBP to the simple monoester MiBP with possible further oxidation to either 2OH-MiBP or 3OH-MiBP. After oxidation a glucuronidation reaction can take place, resulting in MiBP-glucuronide.
Upon entering circulation DiBP is quickly metabolized and excreted through urine, with metabolites reaching peak concentrations 2–4 hours after administration. The main metabolite of DiBP is mono-isobutyl phthalate (MiBP), which makes up 70% of the excretion products. MiBP can be oxidized to either 2OH-mono-isobutyl phthalate (2OH-MiBP) or 3OH-mono-isobutyl phthalate (3OH-MiBP), which make up 20% and 1% of the excretion products respectively. These reactions are likely catalyzed by cytochrome P450 in the liver. The ratio between MiBP and the oxidized metabolites changes depending on the amount of time that has passed since exposure. The ratio between MiBP and 2OH-MiBP and that between MiBP and 3OH-MiBP show a similar trend. With the ratios being high, around 20-30:1, shortly after exposure and dropping gradually as more time passes to rest around 2-5:1. Therefore, a high ratio of oxidized metabolites to the monoester metabolite suggests that there was recent exposure to DiBP, within a few hours of measuring, while a lower ratio suggests that there has been more time since exposure. In addition to oxidation, MiBP can also undergo a glucuronidation reaction, resulting in the metabolite MiBP-glucuronide.
There’s insufficient data to determine if DIBP is associated with acute dermal or inhalation toxicity, eye or dermal irritation, or sensitization. There is evidence on DIBP being a subchronic toxicant. Exposure to the compound can induce changes in body weight, liver weight, reproductive effects, and developmental effects like testicular weight, spermatogenesis, fetal body weight, anogenital distance in male and female rats, and testicular testosterone production, among others.
Biomonitoring studies show that exposures to DIBP have grown recently, presumably as a result of DIBPs use as a substitute for other phthalates such as dibutyl phthalate (DBP) in plastics. In the United States, for instance, the prevalence of MIBP detection in urine has risen from 72% of the general population in 2001–2002 to 96% in 2009–2010, according to data from the National Health and Nutrition Examination Survey (NHANES).
The main issue with phthalate exposure is typically male reproductive toxicity, which is a risk that many phthalates share.
Effect on animals
A study conducted on rats shows that high dosage of DIBP administered by gavage to pregnant female rats between gestational days (GD) 6 and 20, exhibited signs of embryotoxicity and teratogenicity. The growing male reproductive system was negatively impacted by DIBP, which is typical for phthalate esters. When phthalates are exposed in utero during the process of male sexual differentiation, a phenotype known as "phthalate syndrome" is created. This syndrome is characterized by underdevelopment of the male reproductive system, decreased anogenital distance (AGD), retention of the nipple in a female-like manner, and germ cell toxicity, among other things. Therefore, these effects can be connected to decreased insulin-like-3 (INSL3) hormone, which controls transabdominal testicular descent, decreased androgen production in the testicles, which is essential for male sexual development, and disruption of seminiferous cord formation, Sertoli cells, and germ cell development via an unknown mode of action (MOA).
Despite the limited studies in other species, research on zebrafish shows that environmental exposure to DBP and DIBP can have serious consequences for fish offspring. As they go up the food chain and into polluted water, these phthalates can build up in aquatic organisms. Fish are susceptible to environmental toxins in their early lives, whether they are exposed to them directly or indirectly through their parents.
Reductions in fetal plasma leptin levels and in fetal insulin levels. Prenatal exposure disrupts fetal testosterone production in male rats by reducing the expression of several genes and proteins involved in steroidogenesis. In females, increases ovarian aromatase gene expression. DIBP also affected PPAR expression in the liver and testes.
^Yan Y, Zhu F, Zhu C, Chen Z, Liu S, Wang C, Gu C (October 2021). "Dibutyl phthalate release from polyvinyl chloride microplastics: Influence of plastic properties and environmental factors". Water Research. 204: 117597. doi:10.1016/j.watres.2021.117597. PMID34482095.
^Chatterjee S, Dutta TK (September 2003). "Metabolism of butyl benzyl phthalate by Gordonia sp. strain MTCC 4818". Biochemical and Biophysical Research Communications. 309 (1): 36–43. doi:10.1016/S0006-291X(03)01513-4. PMID12943660.
^"Diisobutyl_phthalate". Hazardous Substances Data Bank (HSDB). PubChem, U.S. National Library of Medicine. 5247. Retrieved 2023-03-18.
^Wang C, Zeng T, Gu C, Zhu S, Zhang Q, Luo X (2019). "Photodegradation Pathways of Typical Phthalic Acid Esters Under UV, UV/TiO2, and UV-Vis/Bi2WO6 Systems". Frontiers in Chemistry. 7: 852. doi:10.3389/fchem.2019.00852/full. PMID31921775.
^Lu Y, Tang F, Wang Y, Zhao J, Zeng X, Luo Q, Wang L (September 2009). "Biodegradation of dimethyl phthalate, diethyl phthalate and di-n-butyl phthalate by Rhodococcus sp. L4 isolated from activated sludge". Journal of Hazardous Materials. 168 (2–3): 938–943. doi:10.1016/j.jhazmat.2009.02.126. PMID19342169.
^Lu T, Xue C, Shao J, Gu JD, Zeng Q, Luo S (October 2016). "Adsorption of dibutyl phthalate on Burkholderia cepacia, minerals, and their mixtures: Behaviors and mechanisms". International Biodeterioration & Biodegradation. 114: 1–7. doi:10.1016/j.ibiod.2016.05.015. ISSN0964-8305.
^Huo Y, An Z, Li M, Sun J, Jiang J, Zhou Y, He M (February 2022). "The reaction laws and toxicity effects of phthalate acid esters (PAEs) ozonation degradation on the troposphere". Environmental Pollution. 295: 118692. doi:10.1016/j.envpol.2021.118692. PMID34921942.
^ abcdeChen H, Chen K, Qiu X, Xu H, Mao G, Zhao T, et al. (November 2020). "The reproductive toxicity and potential mechanisms of combined exposure to dibutyl phthalate and diisobutyl phthalate in male zebrafish (Danio rerio)". Chemosphere. 258: 127238. doi:10.1016/j.chemosphere.2020.127238. PMID32563064.
^Feige JN, Gelman L, Tudor C, Engelborghs Y, Wahli W, Desvergne B (May 2005). "Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator-activated receptor/retinoid X receptor heterodimers in the absence and presence of ligand". The Journal of Biological Chemistry. 280 (18): 17880–17890. doi:10.1074/jbc.M500786200. PMID15731109.
^Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, et al. (April 2003). "Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma". Diabetes. 52 (4): 910–917. doi:10.2337/diabetes.52.4.910. PMID12663460.
^Wang YQ, Li YW, Chen QL, Liu ZH (January 2019). "Long-term exposure of xenoestrogens with environmental relevant concentrations disrupted spermatogenesis of zebrafish through altering sex hormone balance, stimulating germ cell proliferation, meiosis and enhancing apoptosis". Environmental Pollution. 244: 486–494. doi:10.1016/j.envpol.2018.10.079. PMID30366296.
^Hair WM, Gubbay O, Jabbour HN, Lincoln GA (July 2002). "Prolactin receptor expression in human testis and accessory tissues: localization and function". Molecular Human Reproduction. 8 (7): 606–11. doi:10.1093/molehr/8.7.606. PMID12087074.
^Li S, Dai J, Zhang L, Zhang J, Zhang Z, Chen B (February 2011). "An association of elevated serum prolactin with phthalate exposure in adult men". Biomedical and Environmental Sciences. 24 (1): 31–39. doi:10.3967/0895-3988.2011.01.004. PMID21440837.
^ abKoch HM, Christensen KL, Harth V, Lorber M, Brüning T (December 2012). "Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses". Archives of Toxicology. 86 (12): 1829–1839. doi:10.1007/s00204-012-0908-1. PMID22820759.
^Carstens L, Cowan AR, Seiwert B, Schlosser D (2020). "Biotransformation of Phthalate Plasticizers and Bisphenol A by Marine-Derived, Freshwater, and Terrestrial Fungi". Frontiers in Microbiology. 11: 317. doi:10.3389/fmicb.2020.00317/full. PMID32180766.
^Jeong SH, Jang JH, Cho HY, Lee YB (November 2020). "Toxicokinetics of diisobutyl phthalate and its major metabolite, monoisobutyl phthalate, in rats: UPLC-ESI-MS/MS method development for the simultaneous determination of diisobutyl phthalate and its major metabolite, monoisobutyl phthalate, in rat plasma, urine, feces, and 11 various tissues collected from a toxicokinetic study". Food and Chemical Toxicology. 145: 111747. doi:10.1016/j.fct.2020.111747. PMID32926938.
^Wittassek M, Wiesmüller GA, Koch HM, Eckard R, Dobler L, Müller J, et al. (May 2007). "Internal phthalate exposure over the last two decades--a retrospective human biomonitoring study". International Journal of Hygiene and Environmental Health. 210 (3–4): 319–333. doi:10.1016/j.ijheh.2007.01.037. PMID17400024.
^ abZota AR, Calafat AM, Woodruff TJ (March 2014). "Temporal trends in phthalate exposures: findings from the National Health and Nutrition Examination Survey, 2001-2010". Environmental Health Perspectives. 122 (3): 235–241. doi:10.1289/ehp.1306681. PMID24425099.
^ abSaillenfait AM, Sabaté JP, Gallissot F (August 2006). "Developmental toxic effects of diisobutyl phthalate, the methyl-branched analogue of di-n-butyl phthalate, administered by gavage to rats". Toxicology Letters. 165 (1): 39–46. doi:10.1016/j.toxlet.2006.01.013. PMID16516415.
^Foster PM, Gray Jr LE (2008). "Casarett and Doull's toxicology: The basic science of poisons". Toxicology: 761–806.
^Lioy PJ, Hauser R, Gennings C, Koch HM, Mirkes PE, Schwetz BA, Kortenkamp A (2015). "Assessment of phthalates/phthalate alternatives in children's toys and childcare articles: Review of the report including conclusions and recommendation of the Chronic Hazard Advisory Panel of the Consumer Product Safety Commission". Journal of Exposure Science & Environmental Epidemiology. 25 (4): 343–353. doi:10.1038/jes.2015.33. PMID25944701.
^ abChen H, Feng W, Chen K, Qiu X, Xu H, Mao G, et al. (June 2021). "Transcriptomic responses predict the toxic effect of parental co-exposure to dibutyl phthalate and diisobutyl phthalate on the early development of zebrafish offspring". Aquatic Toxicology. 235: 105838. doi:10.1016/j.aquatox.2021.105838. PMID33910148.
^Borch J, Axelstad M, Vinggaard AM, Dalgaard M (June 2006). "Diisobutyl phthalate has comparable anti-androgenic effects to di-n-butyl phthalate in fetal rat testis". Toxicology Letters. 163 (3): 183–190. doi:10.1016/j.toxlet.2005.10.020. PMID16458459.
^Howdeshell KL, Wilson VS, Furr J, Lambright CR, Rider CV, Blystone CR, et al. (September 2008). "A mixture of five phthalate esters inhibits fetal testicular testosterone production in the sprague-dawley rat in a cumulative, dose-additive manner". Toxicological Sciences. 105 (1): 153–165. doi:10.1093/toxsci/kfn077. PMID18411233.
^Boberg J, Metzdorff S, Wortziger R, Axelstad M, Brokken L, Vinggaard AM, et al. (September 2008). "Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats". Toxicology. 250 (2–3): 75–81. doi:10.1016/j.tox.2008.05.020. PMID18602967.
^Saillenfait AM, Sabaté JP, Gallissot F (October 2008). "Diisobutyl phthalate impairs the androgen-dependent reproductive development of the male rat". Reproductive Toxicology. 26 (2): 107–115. doi:10.1016/j.reprotox.2008.07.006. PMID18706996.