Diisobutyl phthalate

It is used as a 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.{{cite web | title = Diisobutyl phthalate | id = CHEBI:79053 | work = ChEMBL | publisher = ELIXIR | url = https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:79053 }}

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.{{Cite web | work = Office of Chemical Safety and Pollution Prevention (OCSPP) | publisher = U.S. Environmental Protection Agency|date=2020-04-14 |title=Risk Evaluation for Di-isobutyl Phthalate - (1,2-Benzene- dicarboxylic acid, 1,2- bis-(2methylpropyl) ester) |url=https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/risk-evaluation-di-isobutyl-phthalate-12-benzene |access-date=2023-03-17 |language=en}} DIBP has been detected in various environmental matrices, such as air, water, and sediment. DIBP is known to bioaccumulate in certain aquatic species{{cite journal | vauthors = Yan Y, Zhu F, Zhu C, Chen Z, Liu S, Wang C, Gu C | title = Dibutyl phthalate release from polyvinyl chloride microplastics: Influence of plastic properties and environmental factors | journal = Water Research | volume = 204 | pages = 117597 | date = October 2021 | pmid = 34482095 | doi = 10.1016/j.watres.2021.117597 | bibcode = 2021WatRe.20417597Y }}

DIBP is synthesized by reaction of phthalic anhydride with isobutanol. Various acids are used as a catalyst, such as sulfuric acid, sulfonated graphene, or iron(III) chloride. Water is a byproduct.

Using sulfuric acid, the yield is 61% yield.{{Cite journal | vauthors = Hosangadi BD, Dave RH |date=1996-08-26 |title=An efficient general method for esterification of aromatic carboxylic acids |journal=Tetrahedron Letters |language=en |volume=37 |issue=35 |pages=6375–6378 |doi=10.1016/0040-4039(96)01351-2 |issn=0040-4039}}

File:Acid catalysed reaction of the synthesis of diisobutyl phthalate.jpg

Sulfonated graphene is a heterogeneous catalyst that has several advantages over traditional liquid acids like sulfuric acid.{{Cite journal | vauthors = Garg B, Bisht T, Ling YC |date=2014-10-31 |title=Sulfonated graphene as highly efficient and reusable acid carbocatalyst for the synthesis of ester plasticizers |journal=RSC Advances |language=en |volume=4 |issue=100 |pages=57297–57307 |doi=10.1039/C4RA11205A |bibcode=2014RSCAd...457297G |issn=2046-2069}} Sulfonated graphene can be easily separated from the reaction mixture by filtration and can be reused multiple times without reduction in activity.{{Cite journal | vauthors = Layek RK, Samanta S, Nandi AK |date=2012-03-01 |title=The physical properties of sulfonated graphene/poly(vinyl alcohol) composites |journal=Carbon |language=en |volume=50 |issue=3 |pages=815–827 |doi=10.1016/j.carbon.2011.09.039 |bibcode=2012Carbo..50..815L |issn=0008-6223}} 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.

Lewis acids, such as {{chem2|FeCl3}}, can also be used as the catalyst.{{Cite journal | vauthors = Bajracharya GB, Koju R, Ojha S, Nayak S, Subedi S, Sasai H |date= January 2021 |title=Plasticizers: Synthesis of phthalate esters via FeCl3-catalyzed nucleophilic addition of alcohols to phthalic anhydride |journal=Results in Chemistry |language=en |volume=3 |pages=100190 |doi=10.1016/j.rechem.2021.100190 |s2cid= 240582041 |issn=2211-7156|doi-access=free }} The Lewis acid catalysis process can be run at lower temperatures (50-100 °C), and gives a yield of 86%.

Diisobutyl phthalate is clear, colourless, oily liquid form with a mild odor.{{Cite web |title=Metabocard for Diisobutyl phthalate | id = HMDB0013835 |url=https://hmdb.ca/metabolites/HMDB0013835 |access-date=2023-03-17 | work = The Human Metabolome Database (HMDB) }} It is insoluble in water but soluble in many organic solvents.{{Cite web |title=DI-ISOBUTYL PHTHALATE {{!}} CAMEO Chemicals {{!}} NOAA |url=https://cameochemicals.noaa.gov/chemical/11095 |access-date=2023-03-17 |website=cameochemicals.noaa.gov}}

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).{{Cite web |title=Phthalates - ECHA |url=https://echa.europa.eu/hot-topics/phthalates |access-date=2023-03-17 |website=echa.europa.eu |language=en-GB}} 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.{{cite journal | vauthors = Chatterjee S, Dutta TK | title = Metabolism of butyl benzyl phthalate by Gordonia sp. strain MTCC 4818 | journal = Biochemical and Biophysical Research Communications | volume = 309 | issue = 1 | pages = 36–43 | date = September 2003 | pmid = 12943660 | doi = 10.1016/S0006-291X(03)01513-4 }} This can lead to the breakdown and the eventual degradation of DIBP in the soil and water supply{{Cite web | publisher = PubChem, U.S. National Library of Medicine | title = Diisobutyl_phthalate | work = Hazardous Substances Data Bank (HSDB) | id = 5247 |url= https://pubchem.ncbi.nlm.nih.gov/source/hsdb/5247 |access-date=2023-03-18 }}
• Photodegradation: DIBP can undergo photodegradation by exposure to the sunlight. This can lead to the formation of several degradation products, including phthalic acid, isobutyraldehyde, and other aldehydes.{{cite journal | vauthors = Wang C, Zeng T, Gu C, Zhu S, Zhang Q, Luo X | title = Photodegradation Pathways of Typical Phthalic Acid Esters Under UV, UV/TiO₂, and UV-Vis/Bi₂WO₆ Systems | journal = Frontiers in Chemistry | volume = 7 | pages = 852 | date = 2019 | pmid = 31921775 | doi = 10.3389/fchem.2019.00852 | pmc = 6923729 | doi-access = free }}
• Biodegradation: DIBP can be degraded by microorganisms in soil and in the water. This can transform it into other compounds such as phthalic acid and various isobutyl alcohol derivatives.{{cite journal | vauthors = Lu Y, Tang F, Wang Y, Zhao J, Zeng X, Luo Q, Wang L | title = Biodegradation of dimethyl phthalate, diethyl phthalate and di-n-butyl phthalate by Rhodococcus sp. L4 isolated from activated sludge | journal = Journal of Hazardous Materials | volume = 168 | issue = 2–3 | pages = 938–943 | date = September 2009 | pmid = 19342169 | doi = 10.1016/j.jhazmat.2009.02.126 | bibcode = 2009JHzM..168..938L }}
• Sorption: DIBP can adsorb or sorb onto soil and sediment particles, which can limit its mobility and availability for biological or chemical degradations and reactions.{{Cite journal | vauthors = Lu T, Xue C, Shao J, Gu JD, Zeng Q, Luo S |date= October 2016 |title=Adsorption of dibutyl phthalate on Burkholderia cepacia, minerals, and their mixtures: Behaviors and mechanisms |journal=International Biodeterioration & Biodegradation |language=en |volume=114 |pages=1–7 |doi=10.1016/j.ibiod.2016.05.015 |bibcode= 2016IBiBi.114....1L |issn=0964-8305}}
• Oxidation: DIBP can be oxidized in the presence of ozone or other reactive oxygen species. The formation of various oxidation products, including aldehydes, ketones, and carboxylic acids can be expected{{cite journal | vauthors = Huo Y, An Z, Li M, Sun J, Jiang J, Zhou Y, He M | title = The reaction laws and toxicity effects of phthalate acid esters (PAEs) ozonation degradation on the troposphere | journal = Environmental Pollution | volume = 295 | pages = 118692 | date = February 2022 | pmid = 34921942 | doi = 10.1016/j.envpol.2021.118692 | bibcode = 2022EPoll.29518692H | s2cid = 245248168 }}

These reactions can impact the persistence, bioaccumulation, and toxicity in the environment and may have implications for human and ecosystem health.

The effects of DiBP exposure are mainly realized through its activation of peroxisome proliferator-activated receptor gamma (PPARγ).{{cite journal | vauthors = Chen H, Chen K, Qiu X, Xu H, Mao G, Zhao T, Feng W, Okeke ES, Wu X, Yang L | display-authors = 6 | title = The reproductive toxicity and potential mechanisms of combined exposure to dibutyl phthalate and diisobutyl phthalate in male zebrafish (Danio rerio) | journal = Chemosphere | volume = 258 | pages = 127238 | date = November 2020 | pmid = 32563064 | doi = 10.1016/j.chemosphere.2020.127238 | bibcode = 2020Chmsp.25827238C | s2cid = 219959568 }} PPARs are ligand-activated nuclear transcription factors, the family consists of PPARα, PPARβ/δ and PPARγ.{{cite journal | vauthors = Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, Wahli W | display-authors = 6 | title = International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors | journal = Pharmacological Reviews | volume = 58 | issue = 4 | pages = 726–741 | date = December 2006 | pmid = 17132851 | doi = 10.1124/pr.58.4.5 | s2cid = 2240461 }} There are two isoforms of PPARγ, PPARγ2 is mainly present on cells in adipose tissue, whereas PPARγ1 is found on multiple cells like those in the gut, brain, blood vessels, and some immune and inflammatory cells. Transcriptional regulation through PPARs requires the formation of a heterodimer with retinoid X receptor (RXR). Upon activation by DiBP this PPARγ/RXR heterodimer binds to a DNA sequence called the PPAR response element (PPRE).{{cite journal | vauthors = Feige JN, Gelman L, Tudor C, Engelborghs Y, Wahli W, Desvergne B | title = Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator-activated receptor/retinoid X receptor heterodimers in the absence and presence of ligand | language = English | journal = The Journal of Biological Chemistry | volume = 280 | issue = 18 | pages = 17880–17890 | date = May 2005 | pmid = 15731109 | doi = 10.1074/jbc.M500786200 | doi-access = free }} Binding of the transcription factor to this response element can result in either up- or down-regulation of genes. PPARγ is involved in lipid metabolism and storage as well as glucose metabolism through improving insulin sensitivity,{{cite journal | vauthors = Koutnikova H, Cock TA, Watanabe M, Houten SM, Champy MF, Dierich A, Auwerx J | title = Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 24 | pages = 14457–14462 | date = November 2003 | pmid = 14603033 | pmc = 283613 | doi = 10.1073/pnas.2336090100 | doi-access = free | bibcode = 2003PNAS..10014457K }}{{cite journal | vauthors = Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, Williams RL, Umpleby AM, Thomas EL, Bell JD, Dixon AK, Dunne F, Boiani R, Cinti S, Vidal-Puig A, Karpe F, Chatterjee VK, O'Rahilly S | display-authors = 6 | title = Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma | journal = Diabetes | volume = 52 | issue = 4 | pages = 910–917 | date = April 2003 | pmid = 12663460 | doi = 10.2337/diabetes.52.4.910 | doi-access = free }} so binding of DiBP leads to altered leptin and insulin levels. DiBP also leads to a down-regulation of proteins involved in steroid production, resulting in higher levels of androgenic hormones.

Another type of pathway affected by DiBP exposure is the cytokine-cytokine receptor pathway. There are two pathways affected: the tumour necrosis factor receptor superfamily (TNFRSF) and the prolactin receptor pathway, both of which affect spermatogenesis. In zebra fish, there are two types of TNFRSF: tnfrsf1a and tnfrsf1b, the latter of which is down-regulated by DiBP. Tnfrsf1b is involved in regeneration and tissue repair and its down-regulation has been shown to increase apoptosis of sperm cells.{{cite journal | vauthors = Wang YQ, Li YW, Chen QL, Liu ZH | title = 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 | journal = Environmental Pollution | volume = 244 | pages = 486–494 | date = January 2019 | pmid = 30366296 | doi = 10.1016/j.envpol.2018.10.079 | bibcode = 2019EPoll.244..486W | s2cid = 53112695 }} Prolactin (PLR) on the other hand is up-regulated as a result of DiBP exposure. Prolactin has many roles, including roles in cell regeneration and regulation of the male reproductive system.{{cite journal | vauthors = Hair WM, Gubbay O, Jabbour HN, Lincoln GA | title = Prolactin receptor expression in human testis and accessory tissues: localization and function | journal = Molecular Human Reproduction | volume = 8 | issue = 7 | pages = 606–11 | date = July 2002 | pmid = 12087074 | doi = 10.1093/molehr/8.7.606 | doi-access = free }} High PLR concentrations as a result of phthalate exposure has been linked to reduced sperm concentrations in both adult men and zebra fish.{{cite journal | vauthors = Li S, Dai J, Zhang L, Zhang J, Zhang Z, Chen B | title = An association of elevated serum prolactin with phthalate exposure in adult men | journal = Biomedical and Environmental Sciences | volume = 24 | issue = 1 | pages = 31–39 | date = February 2011 | pmid = 21440837 | doi = 10.3967/0895-3988.2011.01.004 | bibcode = 2011BioES..24...31L }}

File:DIBP_Metabolism.jpgUpon entering circulation DiBP is quickly metabolized and excreted through urine, with metabolites reaching peak concentrations 2–4 hours after administration.{{cite journal | vauthors = Koch HM, Christensen KL, Harth V, Lorber M, Brüning T | title = Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses | journal = Archives of Toxicology | volume = 86 | issue = 12 | pages = 1829–1839 | date = December 2012 | pmid = 22820759 | doi = 10.1007/s00204-012-0908-1 | s2cid = 253718517 }} 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.{{cite journal | vauthors = Carstens L, Cowan AR, Seiwert B, Schlosser D | title = Biotransformation of Phthalate Plasticizers and Bisphenol A by Marine-Derived, Freshwater, and Terrestrial Fungi | journal = Frontiers in Microbiology | volume = 11 | pages = 317 | date = 2020 | pmid = 32180766 | doi = 10.3389/fmicb.2020.00317 | pmc = 7059612 | doi-access = free }} 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.{{cite journal | vauthors = Jeong SH, Jang JH, Cho HY, Lee YB | title = 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 | journal = Food and Chemical Toxicology | volume = 145 | pages = 111747 | date = November 2020 | pmid = 32926938 | doi = 10.1016/j.fct.2020.111747 }}

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.{{Cite web |date=2010 |title=Toxicity review of diisobutyl phthalate (DiBP) |url=https://www.cpsc.gov/PageFiles/125773/dibp.pdf | archive-url = https://web.archive.org/web/20130420132018/https://www.cpsc.gov/PageFiles/125773/dibp.pdf | archive-date = 20 April 2013 |access-date=2023-03-17 |website=www.cpsc.gov}}

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.{{cite journal | vauthors = Wittassek M, Wiesmüller GA, Koch HM, Eckard R, Dobler L, Müller J, Angerer J, Schlüter C | display-authors = 6 | title = Internal phthalate exposure over the last two decades--a retrospective human biomonitoring study | journal = International Journal of Hygiene and Environmental Health | volume = 210 | issue = 3–4 | pages = 319–333 | date = May 2007 | pmid = 17400024 | doi = 10.1016/j.ijheh.2007.01.037 | bibcode = 2007IJHEH.210..319W }}{{cite journal | vauthors = Zota AR, Calafat AM, Woodruff TJ | title = Temporal trends in phthalate exposures: findings from the National Health and Nutrition Examination Survey, 2001-2010 | journal = Environmental Health Perspectives | volume = 122 | issue = 3 | pages = 235–241 | date = March 2014 | pmid = 24425099 | doi = 10.1289/ehp.1306681 | pmc = 3948032 }} 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.{{cite journal | vauthors = Yost EE, Euling SY, Weaver JA, Beverly BE, Keshava N, Mudipalli A, Arzuaga X, Blessinger T, Dishaw L, Hotchkiss A, Makris SL | display-authors = 6 | title = Hazards of diisobutyl phthalate (DIBP) exposure: A systematic review of animal toxicology studies | journal = Environment International | volume = 125 | pages = 579–594 | date = April 2019 | pmid = 30591249 | pmc = 8596331 | doi = 10.1016/j.envint.2018.09.038 | bibcode = 2019EnInt.125..579Y }}

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.{{cite journal | vauthors = Saillenfait AM, Sabaté JP, Gallissot F | title = Developmental toxic effects of diisobutyl phthalate, the methyl-branched analogue of di-n-butyl phthalate, administered by gavage to rats | journal = Toxicology Letters | volume = 165 | issue = 1 | pages = 39–46 | date = August 2006 | pmid = 16516415 | doi = 10.1016/j.toxlet.2006.01.013 }} 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.{{Cite journal | vauthors = Foster PM, Gray Jr LE |date=2008 |title=Casarett and Doull's toxicology: The basic science of poisons |url= |journal=Toxicology |volume= |issue= |pages=761–806 |doi= |issn=}}{{cite journal | vauthors = Lioy PJ, Hauser R, Gennings C, Koch HM, Mirkes PE, Schwetz BA, Kortenkamp A | title = 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 = Journal of Exposure Science & Environmental Epidemiology | volume = 25 | issue = 4 | pages = 343–353 | date = 2015 | pmid = 25944701 | doi = 10.1038/jes.2015.33 | s2cid = 19276318 | doi-access = free }}{{Cite book | author = National Research Council (U.S.). Committee on the Health Risks of Phthalates. National Academies Press |url=http://worldcat.org/oclc/586808833 |title=Phthalates and cumulative risk assessment : the task ahead |date=2008 |publisher=National Academies Press |isbn=978-0-309-12841-4 |oclc=586808833}} 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).{{cite journal | vauthors = Johnson KJ, Heger NE, Boekelheide K | title = Of mice and men (and rats): phthalate-induced fetal testis endocrine disruption is species-dependent | journal = Toxicological Sciences | volume = 129 | issue = 2 | pages = 235–248 | date = October 2012 | pmid = 22700540 | doi = 10.1093/toxsci/kfs206 | pmc = 3491958 }}{{cite journal | vauthors = Martino-Andrade AJ, Chahoud I | title = Reproductive toxicity of phthalate esters | journal = Molecular Nutrition & Food Research | volume = 54 | issue = 1 | pages = 148–157 | date = January 2010 | pmid = 19760678 | doi = 10.1002/mnfr.200800312 }}

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.

• Phthalates
• Dibutyl phthalate
• Phthalic anhydride
• Isobutanol

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• {{ICSC|0829|08}}

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Category:Phthalate esters

Category:Plasticizers

Category:Isobutyl esters