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.[1] DIBP can be absorbed via oral ingestion and dermal exposure.[2] 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).[2]
History
In 1836 French chemist
Auguste Laurent oxidized
naphthalene with
chromic acid and created
phthalic anhydride, of which phthalates are derived.[3]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.[1] Due to the increase in human exposure to phthalates, in 1999 the European Union restricted the use of some of them in children's toys.[4]
Legislation
Date
Action
References
December 14, 2005
The European Union restricted phthalates from several children's toys.
It is used as a
plasticizer additive in a range of plastic and rubber materials.[2] 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.[9] It is dense and water-insoluble.[10]
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.[2] 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.[9] DIBP has been detected in various environmental matrices, such as air, water, and
sediment. DIBP is known to
bioaccumulate in certain aquatic species[11]
Sulfonated graphene is a
heterogeneous catalyst that has several advantages over traditional liquid acids like sulfuric acid.[13] Sulfonated graphene can be easily separated from the reaction mixture by
filtration and can be reused multiple times without reduction in activity.[14] 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.[13]
Lewis acids, such as FeCl3, can also be used as the catalyst.[15] The
Lewis acid catalysis process can be run at lower temperatures (50-100 °C), and gives a yield of 86%.[15]
Available forms
Diisobutyl phthalate is clear, colourless, oily liquid form with a mild odor.[16] It is insoluble in water but soluble in many organic solvents.[17]
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).[18] It may be used as a component in formulations of several products including
adhesives, paints, coatings and lubricants.[9] 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.[9] In many of these products DIBP is now prohibited to be used in formulations according to
REACH.[18]
Environmental reactions
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.[19] This can lead to the breakdown and the eventual degradation of DIBP in the soil and water supply[20]
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.[21]
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.[23]
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[24]
These reactions can impact the persistence,
bioaccumulation, and toxicity in the environment and may have implications for human and
ecosystem health.
Mechanisms of actions
PPARγ Pathway
The effects of DiBP exposure are mainly realized through its activation of
peroxisome proliferator-activated receptor gamma (PPARγ).[25] PPARs are
ligand-activated nuclear transcription factors, the family consists of
PPARα, PPARβ/δ and PPARγ.[26] 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).[27] 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,[28][29] 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.[25]
Cytokine-cytokine receptor pathway
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.[25] 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.[30]Prolactin (PLR) on the other hand is up-regulated as a result of DiBP exposure.[25] Prolactin has many roles, including roles in cell regeneration and regulation of the
male reproductive system.[31] High PLR concentrations as a result of phthalate exposure has been linked to reduced sperm concentrations in both adult men and zebra fish.[32][25]
Metabolism
Upon entering circulation DiBP is quickly
metabolized and excreted through
urine, with
metabolites reaching peak concentrations 2–4 hours after administration.[33] 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.[34] The ratio between MiBP and the oxidized metabolites changes depending on the amount of time that has passed since exposure.[33] 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.[35]
Toxicity
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.[36]
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.[37][38] 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).[38]
The main issue with phthalate exposure is typically male reproductive toxicity, which is a risk that many phthalates share.[39]
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.[40] 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.[41][42][43] 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).[43][44][45]
Despite the limited studies in other species, research on
zebrafish[46] 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.
Pregnant females: Transient decrease in body weight gain, observed at 500 mg/kg and higher. Embryolethality and
teratogenicity at 750 and 1000 mg/kg.
Male fetuses: Undescended testis at 500 mg/kg. The degree of transabdominal migration of testis in relation to the bladder were disturbed at 500 mg/kg and above.
Parental individual DIBP exposure disturbed key genes in
circadian rhythm and phototransduction signal pathways, which could influence the eye development of F1 larvae.
Disrupt fetal testicular development. AGD was reduced at GD 19 and GD 20/21 in males and increased in females exposed to DIBP. It also reduced bodyweights of male and female fetuses.
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.
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