Benzyl butyl phthalate

Last updated
Benzyl butyl phthalate
Benzyl butyl phthalate.svg
Benzyl-butyl-phthalate-3D-balls.png
Names
Preferred IUPAC name
Benzyl butyl benzene-1,2-dicarboxylate
Other names
Benzylbutylphthalate; n-Butyl benzyl phthalate; BBP
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.001.475 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 201-622-7
KEGG
PubChem CID
RTECS number
  • TH9990000
UNII
UN number 3082
  • InChI=1S/C19H20O4/c1-2-3-13-22-18(20)16-11-7-8-12-17(16)19(21)23-14-15-9-5-4-6-10-15/h4-12H,2-3,13-14H2,1H3 Yes check.svgY
    Key: IRIAEXORFWYRCZ-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C19H20O4/c1-2-3-13-22-18(20)16-11-7-8-12-17(16)19(21)23-14-15-9-5-4-6-10-15/h4-12H,2-3,13-14H2,1H3
    Key: IRIAEXORFWYRCZ-UHFFFAOYAR
  • CCCCOC(=O)c1ccccc1C(=O)OCc2ccccc2
Properties
C19H20O4
Molar mass 312.365 g·mol−1
Density 1.119 g cm−3 [1]
Melting point −35 °C (−31 °F; 238 K)
Boiling point 370 °C (698 °F; 643 K)
Hazards
GHS labelling:
GHS-pictogram-silhouette.svg GHS-pictogram-pollu.svg
Danger
H360, H410
P201, P202, P273, P281, P308+P313, P391, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Benzyl butyl phthalate (BBP) is an organic compound historically used a plasticizer, but which has now been largely phased out due to health concerns. It is a phthalate ester of containing benzyl alcohol, and n-butanol tail groups. Like most phthalates, BBP is non-volatile and remains liquid over a wide range of temperatures. It was mostly used as a plasticizer for PVC, but was also a common plasticizer for PVCA and PVB.

Contents

BBP was commonly used as a plasticizer for vinyl foams, which are often used as sheet vinyl flooring and tiles. Compared to other phthalates it was less volatile than dibutyl phthalate and imparted better low temperature flexibility than di(2-ethylhexyl) phthalate. [2]

BBP is classified as toxic by the European Chemical Bureau (ECB) and hence its use in Europe has declined rapidly.

Structure and reactivity

BBP is a diester. Since BBP contains two ester bonds it can react in a variety of chemical pathways. Both the carbonyl C-atoms are weakly electrophilic and therefore targets for attacks by strong nucleophilic compounds. Besides the carbonyl C-atom target, it contains a C-H bond whereas the H-atom is weakly acidic, which makes it susceptible for deprotonation by a strong base. BBP is hydrolyzed under either acidic or basic conditions. The hydrolysis under acidic conditions is a reversion of the Fischer-Speier esterification, whereas the hydrolysis under basic conditions is performed by saponification. Since BBP contains two ester bonds it is difficult to perform a chemoselective reaction.

Under basic conditions BBP can undergo saponification. The saponification number of BBP is 360 mg KOH/g. The amount of carboxylic functional groups per molecule are relatively high (2 carboxylic functional groups with a molecular weight of 312.36). This makes the compound relatively unsaponifiable. [3]

Synthesis

Concentrated sulfuric acid dehydrates n-butyl alcohol to yield 1-butene, which reacts with phthalic anhydride to produce n-butyl phthalate. Phthalic anhydride does react directly with 1-butanol to form this same intermediate, but further reaction to form dibutyl phthalate does occur to a significant extent. Carrying out the procedure using 1-butene avoids this side reaction. Monobutyl phthalate is isolated and then added to a mixture of benzyl bromide in acetone in the presence of potassium carbonate (to keep the pH high to facilitate the substitution reaction required to form the second ester linkage), from which BBP can then be isolated. [4]

Metabolism

BBP can be absorbed by the human body in a variety of ways. First of all, it can be taken up dermally, meaning that the compound is absorbed by the skin. Studies in rats show that 27% of the uptake of BBP occurs via this route. [5] During this process, the structure of the phthalate diester determines the degree of dermal absorption.

BBP can also be taken up orally. The amount of the compound that is being absorbed by the body depends on the dose that has been administered. Absorption seems to be limited at high doses, [6] meaning that small amounts are taken up more easily than great amounts. Finally, BBP can be inhaled. In this case, BBP is absorbed via the lungs.

BBP is biotransformed in the human body in numerous of ways. Gut esterases metabolize BBP to monoester metabolites. Those are mainly monobutyl and mono-benzyl phthalate (MBzP) plus small amounts of mono-n-butyl phthalate. [7] The ratio of monobutyl to monobenzyl phthalate has been determined to be 5:3. [8] These metabolites can be absorbed and excreted directly or undergo a phase II reaction. In the latter, they are conjugated with glucuronic acid and then excreted as glucuronate. Studies in rats have shown that 70% of BBP is not conjugated while 30% is conjugated. At high concentrations of BBP, relatively less metabolite is conjugated. This indicates that the conjugation pathway (glucuronidation) is saturated at high amounts of administered BBP. The metabolites of BBP are excreted rapidly, 90% of them has left the body within 24 hours. As a consequence, the half-life of BBP in the blood is quite low and counts up to only 10 minutes. [9] However, monoester metabolites of BBP (such as monophthalate) have a longer half-life of 6 hours. [6]

BBP is metabolized quite efficiently within the body. While a major part of the BBP is excreted as a mono-benzyl phthalate metabolite, a minor fragment of the BBP is excreted in the form of mono-butyl phthalate. [9] BBP is rarely found in the bile in its original form. Nevertheless, metabolites like monobutyl glucuronide and monobenzyl phthalate glucuronide as well as trace amounts of free monoesters can be found there.

Mode of action

Relatively little is known about the modes of action of BBP. Experimental research does hint at a number of mechanisms, though. One phenomenon is that BBP binds to the estrogen receptor of rats. [10] In vitro-experiments do show a weak potential of BBP to have an influence on estrogen-mediated gene expression. This is because phthalates like BBP are mimicking estrogens. Metabolites of BBP, on the other hand, are only weakly reactive with the estrogen receptor. [11] Not much is known about if and how this mechanism plays out in vivo.

Furthermore, BBP binds to intracellular steroid receptors and causes genomic effects by doing so. BBP also interferes with ion-channel receptors which cause non-genomic effects. [12] The underlying mechanism is that BBP blocks the calcium signaling that is coupled with P2X receptors. Calcium signaling, mediated via P2X, eventually has an influence in cell proliferation and bone remodeling. During developmental phases of bone remodelling, high environmental exposure of BBP might therefore pose a problem.

Exposure

The exposure of the general population to BBP has been estimated by several authorities. One of the authorities, the International Program on Chemical Safety (IPCS), came to the conclusion that exposure to BBP is mainly caused by food intake. BBP, as many other phthalates, is used to increase the flexibility of plastics. However, phthalates are not bound to the plastics which means that they can easily be released into the environment. From there it can be taken up into food during crop cultivation. Alternatively, BBP can enter food via food packaging materials. [13] Moreover, children may be exposed to BBP by mouthing of toys. [14] Various studies by authorities, between the 1980s and 2000s, have been done to estimate the general population exposure to BBP in different countries with varying results. The adult exposure was estimated to be 2 μg/kg body weight/day in the U.S. [14] BBP exposure to children is likely to be higher due to differences in food intake. Nonetheless, these estimates should be interpreted with caution as they are based on different food types, different assumptions were used in calculations, levels of BBP in food vary in different countries and levels of BBP in food changes over time. Next to general exposure there is also occupation-related exposure to BBP . This can occur via inhalation of vapors or via skin contact. This has been estimated to be 286 μg/kg body weight/day. However, in general the occupational exposure is thought be lower than this. [14] The NOAEL of BBP was experimentally found to be 50 mg/kg body weight/day and the associated margin of safety is ca. 4,800 or more. [15] Thus, BBP does not seem to pose a very high risk under conditions of general or occupational exposure based on current estimates.

Toxicity and adverse effects

No primary irritation or sensitization reactions were found in a patch test involving 200 volunteers. However, if BBP is taken up by the body it can exert toxic effects. It has a LD50 for rats ranging from 2 to 20 g/kg body weight. [16]

Occupational hazards

Workers in the PVC processing industry are exposed to higher levels of BBP than the general public and are thus more at risk of experiencing negative health effects. No effects of the respiratory or peripheral nerve system have been observed in workers. Although slightly higher levels of BBP metabolites were found in their urine. [17] [ full citation needed ] Long-term occupational exposure to BBP does, however, significantly increase the risk of multiple myeloma. [14]

Children

Children are possibly exposed to higher levels of BBP than adults. Since children form a vulnerable group for chemical exposure, studies have been conducted to evaluate the effects of BBP exposure. PVC flooring has been linked to a significant increase in the risk of bronchial obstruction in the first two years of life [14] and in the development of language delay in pre-school aged children. [18] BBP has also been positively associated with airway inflammation in children living in urban areas. [19] Moreover, there is evidence suggesting that prenatal exposure to BBP coming from in house dust affects the risk of childhood eczema. [19] The exact mechanism of how phthalates and their metabolites reach the fetus remain unclear. However, since these chemicals seem to be able to reach the fetus they are thought to affect fetal health and development. [20] Further research is needed to establish the effect of prenatal exposure on fetal development.

Teratogenicity and reproductive effects

Only a few studies have been done on reproductive effects of BBP on humans, but the results are inconclusive. According to the NTP-CERHR the adverse reproductive effects are negligible for exposed men. Yet, one study found a link between altered semen quality and exposure to monobutyl phthalate, a major metabolite of BBP. [21] No research has been done on the teratogenic effects of BBP on humans. However, numerous studies have been conducted with animals. Prenatal exposure to high levels of BBP in rats can lead to lower fetal body weight, increased incidence of fetal malformations, post-implantation loss and even embryonic death. [22] [23] [24] The precise teratogenic effects observed in rat fetuses seem to be related to the period of exposure in development. Exposure to BBP in the first half of pregnancy lead to embryolethality while exposure in the second half to teratogenicity. [24]

In a two-generational study male offspring were found to have macroscopic and microscopic changes in the testes, decreased serum testosterone concentrations in addition to reduced sperm production. [25] Additionally, reduced seminal vesicle weight has been observed. [14] These results indicate a clear negative effect on the fertility.

Other toxicity studies in animals

Numerous studies have been carried out in animals to elucidate the adverse effects of BBP exposure. Long-term BBP exposure in rats leads to reduced body weight, increased weight of the liver and kidneys and carcinogenicity. [14] [22] [25] In male rats the incidence of pancreatic tumors increased while in female rats the incidence for both pancreatic and bladder tumors increased. [26] Although BBP has been linked to carcinogenicity, studies indicate that BBP is not genotoxic. [22]

Environmental toxicology

BBP, like other low molecular weight phthalate esters, is toxic to aquatic organisms. This includes unicellular freshwater green algae such as Selenastrum capricornutum. BBP has also been shown to be toxic to freshwater invertebrates like D. magna. For these organisms, the toxic effect correlates with the water solubility of the phthalate which is relatively high for BBP compared to high molecular weight phthalates. BBP affects saltwater invertebrates significantly. Experiments with mysid shrimp show that BBP is acutely toxic to these organisms. Among the species of fish, the sweetwater fish bluegills were shown to be toxically affected by BBP. Furthermore, a rapid lethal effect has been observed for the saltwater fish Parophrys vetulus. [27]

Degradation

When the degradation of BBP is taken into consideration, one should be aware of the fact that it contains two ester functional groups. This gives organisms a handle for biotransformations. The ester groups gives BBP hydrophilic properties and will therefore hydrolyze fairly easy. Following an examination performed in 1997, [28] it was found that biotransformations play a very important role in the degeneration of BBP. Furthermore, the solubility in water plays a significant role in the effectiveness of biotransformation in an environment. The butyl group gives BBP a slightly more hydrophobic property, compared to other plasticizer it is relatively good soluble. The longer the alkyl chain the less soluble and the less well it is degenerated.

Legislation measures

BBP was listed as a developmental toxicant under California's Proposition 65 on December 2, 2005. [29] California's Office of Environmental Health Hazard Assessment (OEHHA), on July 1, 2013, approved a Maximum Allowable Dose Level of 1,200 micrograms per day for BBP. [30] Canadian Authorities have restricted the usage of phthalates, including BBP, in soft vinyl children's toys and child care articles. [31]

According to EU Council Directive 67/548/EEC1, BBP is classified as reproductive toxicant and therefore restricted in use. The restriction covers the placing on the market and use in any type of toys and childcare articles. These restrictions are in place since 16 January 2017. Due to the classification and labelling of BBP companies have moved to the use of alternatives. Restrictions are not limited to toys. Since 22 November 2006 cosmetic products containing BBP shall not be supplied to consumers in the EU. [32]

Related Research Articles

Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by teratogens. Teratogens are substances that may cause non-heritable birth defects via a toxic effect on an embryo or fetus. Defects include malformations, disruptions, deformations, and dysplasia that may cause stunted growth, delayed mental development, or other congenital disorders that lack structural malformations. The related term developmental toxicity includes all manifestations of abnormal development that are caused by environmental insult. The extent to which teratogens will impact an embryo is dependent on several factors, such as how long the embryo has been exposed, the stage of development the embryo was in when exposed, the genetic makeup of the embryo, and the transfer rate of the teratogen.

<span class="mw-page-title-main">Phthalates</span> Any ester derived from phthalic acid

Phthalates, or phthalate esters, are esters of phthalic acid. They are mainly used as plasticizers, i.e., substances added to plastics to increase their flexibility, transparency, durability, and longevity. They are used primarily to soften polyvinyl chloride (PVC). Note that while phthalates are usually plasticizers, not all plasticizers are phthalates. The two terms are specific and unique and cannot be used interchangeably.

<span class="mw-page-title-main">Benzyl alcohol</span> Aromatic alcohol

Benzyl alcohol (also known as α-cresol) is an aromatic alcohol with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn" (not to be confused with "Bz" which is used for benzoyl), thus benzyl alcohol is denoted as BnOH. Benzyl alcohol is a colorless liquid with a mild pleasant aromatic odor. It is useful as a solvent for its polarity, low toxicity, and low vapor pressure. Benzyl alcohol has moderate solubility in water (4 g/100 mL) and is miscible in alcohols and diethyl ether. The anion produced by deprotonation of the alcohol group is known as benzylate or benzyloxide.

<span class="mw-page-title-main">Endocrine disruptor</span> Chemicals that can interfere with endocrine or hormonal systems

Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine systems. These disruptions can cause numerous adverse human health outcomes, including alterations in sperm quality and fertility; abnormalities in sex organs‚ endometriosis‚ early puberty‚ altered nervous system or immune function; certain cancers; respiratory problems; metabolic issues; diabetes, obesity, or cardiovascular problems; growth, neurological and learning disabilities, and more. Found in many household and industrial products, endocrine disruptors "interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of homeostasis ."

<span class="mw-page-title-main">Anogenital distance</span> Distance from midpoint of the anus to the genitalia

Anogenital distance (AGD) is the distance from the midpoint of the anus to the genitalia, the underside of the vagina, the clitoris or the scrotum. It is considered medically significant for a number of reasons, in both humans and other animals, including sex determination and as a marker of endocrine disruptor exposure. It is regulated by dihydrotestosterone, which can be disrupted by phthalates common in plastics.

Xenoestrogens are a type of xenohormone that imitates estrogen. They can be either synthetic or natural chemical compounds. Synthetic xenoestrogens include some widely used industrial compounds, such as PCBs, BPA, and phthalates, which have estrogenic effects on a living organism even though they differ chemically from the estrogenic substances produced internally by the endocrine system of any organism. Natural xenoestrogens include phytoestrogens which are plant-derived xenoestrogens. Because the primary route of exposure to these compounds is by consumption of phytoestrogenic plants, they are sometimes called "dietary estrogens". Mycoestrogens, estrogenic substances from fungi, are another type of xenoestrogen that are also considered mycotoxins.

<span class="mw-page-title-main">Bis(2-ethylhexyl) phthalate</span> Organic compound used as a plasticizer to soften polymer matrix

Bis(2-ethylhexyl) phthalate (di-2-ethylhexyl phthalate, diethylhexyl phthalate, diisooctyl phthalate, DEHP; incorrectly — dioctyl phthalate, DIOP) is an organic compound with the formula C6H4(CO2C8H17)2. DEHP is the most common member of the class of phthalates, which are used as plasticizers. It is the diester of phthalic acid and the branched-chain 2-ethylhexanol. This colorless viscous liquid is soluble in oil, but not in water.

<span class="mw-page-title-main">Diisobutyl phthalate</span> Chemical compound

Diisobutyl phthalate (DIBP) is a phthalate ester having the structural formula C6H4(COOCH2CH 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 exposure. 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).

<span class="mw-page-title-main">Dimethyl phthalate</span> Chemical compound

Dimethyl phthalate (DMP) is an organic compound and phthalate ester. it is a colourless and oily liquid that is soluble in organic solvents, but which is only poorly soluble in water.

<span class="mw-page-title-main">Benzotrichloride</span> Chemical compound

Benzotrichloride (BTC), also known as α,α,α-trichlorotoluene, phenyl chloroform or (trichloromethyl)benzene, is an organic compound with the formula C6H5CCl3. Benzotrichloride is an unstable, colorless or somewhat yellowish, viscous, chlorinated hydrocarbon with a penetrating odor. Benzotrichloride is used extensively as a chemical intermediate for products of various classes, i.e. dyes and antimicrobial agents.

<span class="mw-page-title-main">Obesogen</span> Foreign chemical compound that disrupts lipid balance causing obseity

Obesogens are certain chemical compounds that are hypothesised to disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity. Obesogens may be functionally defined as chemicals that inappropriately alter lipid homeostasis and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity.

<span class="mw-page-title-main">Diethyl phthalate</span> Chemical compound

Diethyl phthalate (DEP) is a phthalate ester. It occurs as a colourless liquid without significant odour but has a bitter, disagreeable taste. It is more dense than water and insoluble in water; hence, it sinks in water.

Bis(2-ethylhexyl) terephthalate commonly abbreviated DEHT (Dioctyl terephthalate or DOTP), is an organic compound with the formula C6H4(CO2C8H17)2. It is a non-phthalate plasticizer, being the diester of terephthalic acid and the branched-chain 2-ethylhexanol, which is often generically referred to as octyl. This colorless viscous liquid is used for softening PVC plastics and is known for chemical similarity to general purpose phthalates such as DEHP and DINP, but without any negative regulatory pressure. It possesses very good plasticizing properties and may be used as a direct replacement for DEHP and DINP in many applications.

<span class="mw-page-title-main">Developmental toxicity</span>

Developmental toxicity is any developmental malformation that is caused by the toxicity of a chemical or pathogen. It is the structural or functional alteration, reversible or irreversible, which interferes with homeostasis, normal growth, differentiation, development or behavior. Developmental toxicity is caused by environmental insult, which includes drugs, alcohol, diet, toxic chemicals, and physical factors.

Methacrylonitrile, MeAN in short, is a chemical compound that is an unsaturated aliphatic nitrile, widely used in the preparation of homopolymers, copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. MeAN is also used as a replacement for acrylonitrile in the manufacture of an acrylonitrile/butadiene/styrene-like polymer. It is a clear and colorless liquid, that has a bitter almond smell.

<span class="mw-page-title-main">Triazofos</span> Chemical compound

Triazofos is a chemical compound used in acaricides, insecticides, and nematicides.

Joseph F. Holson, an American scientist, business executive, and educator in the disciplines of toxicology and product development, served as President of WIL Research Laboratories for 20 years (1988-2008). He is known for his contributions to the fields of developmental and reproductive toxicology (DART), pharmacokinetics, and risk assessment, including extensive experience with study design, data interpretation, and interspecies extrapolation of health effects data. He has served in numerous U.S. EPA/FDA advisory committees and as an expert toxicology witness. He was elected to two National Academy of Sciences toxicology committees. Dr. Holson is an editor and author of the textbook Regulatory Toxicology and an author of two significant chapters in the textbook Developmental and Reproductive Toxicology: A Practical Approach, Second Edition. Two of his peer-reviewed articles were recognized by the Risk Assessment Specialty Section of the Society of Toxicology as the Outstanding Published Papers Demonstrating an Application of Risk Assessment. He is the first author to receive this award in consecutive years for publications produced with two separate sets of coauthors.

Antiandrogens in the environment have become a topic of concern. Many industrial chemicals, including phthalates and pesticides, exhibit antiandrogen activity in animal experiments. Certain plant species have also been found to produce antiandrogens. In animal studies, environmental antiandrogens can harm reproductive organ development in fetuses exposed in utero as well as their offspring.

<span class="mw-page-title-main">Monobutyl phthalate</span> Chemical compound

Monobutyl phthalate (MBP) is an organic compound with the condensed structural formula CH3(CH2)3OOCC6H4COOH. It is a white solid that features both an butyl ester group and a carboxylic acid group. It is the major metabolite of dibutyl phthalate. Like many phthalates, MBP has attracted attention as a potential endocrine disruptor.

<span class="mw-page-title-main">Monobenzyl phthalate</span> Chemical compound

Monobenzyl phthalate (MBzP) also known as 1,2-Benzenedicarboxylic acid, 1-(phenylmethyl) ester is an organic compound with the condensed structural formula C6H5CH2OOCC6H4COOH. It is the major metabolite of butyl benzyl phthalate(BBP), a common plasticizer. BBP can also be metabolized into monobutyl phthalate (MBP). Like many phthalates, BBP has attracted attention as a potential endocrine disruptor.

References

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  2. ↑ Gachter, R.; Muller, H. (1987). Plastics additives handbook : stabilizers, processing aids, plasticizers, fillers, reinforcements, colorants for thermoplastics (2nd ed.). Munich: Hanser Publishers. p. 273. ISBN   3-446-15072-2.
  3. ↑ "ADD |LANXESS Additives Business Unit" (PDF). Archived from the original (PDF) on 2007-09-28.
  4. ↑ Cheng, Kur-Ta; Rajasekhar, Dodda; Huang, Sheng-Tung; Hsu, Feng-Lin; Subbaraju, Gottumukkala (2003). "Revised structure for spatozoate, a metabolite of Spatoglossum variabile" (PDF). Indian Journal of Chemistry, Section B . 42 (5): 1190–1192.
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  6. 1 2 Eigenberg D.A. Bozigian H.P. Carter D.E. Sipes I.G. Distribution excretion and metabolism of butylbenzyl phthalate in the rat (1986). J. Toxicol. Environ. Health. 17, 445–456
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  8. ↑ Mikuriya, H & Ikemoto, I & Tanaka, A. (1988) Urinary metabolites contributing to testicular damage induced by butylbenzyl phthalate. Jikeikai Medical Journal. 35. 403-409.
  9. 1 2 DHHS/NTP-CERHR (2003). Monograph on the Potential Human Reproductive and Developmental Effects of Butyl Benzyl Phthalate (BBP). NIH Publication No. 03-4487. This shows that most of the BBP is rapidly metabolized to monoester components and then excreted
  10. ↑ Zacharewski, T. (1998). Examination of the in vitro and in vivo estrogenic activities of eight commercial phthalate esters. Toxicol Sci. 46 (2), 282-93
  11. ↑ Picard, K. et al. (2001). Estrogenic Activity and Metabolism of N-Butyl Benzyl Phthalate in Vitro: Identification of the Active Molecule(s). Toxicology and Applied Pharmacology 172 (2), 108-118
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  14. 1 2 3 4 5 6 7 NTP - CERHR. (2003). NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Butyl Benzyl Phthalate ( BBP )
  15. ↑ "Evaluation Of New Scientific Evidence Concerning The Restrictions Contained In Annex XVII To Regulation (EC) NO 1907/2006 (REACH)". European Chemicals Agency. July 2010. Archived from the original on 4 November 2021. Retrieved 3 November 2022.
  16. ↑ Meek, M. (1999). BUTYL BENZYL PHTHALATE. [ebook] Stuttgart: United Nations Environment Programme, the International Labour Organisation, and the World Health Organisation, p.9. Available at: http://www.who.int/ipcs/publications/cicad/en/cicad17.pdf
  17. ↑ Nielsen, Aekesson, & Skerfving, 1985
  18. ↑ Bornehag, Carl-Gustaf; Lindh, Christian; Reichenberg, Abraham; Wikström, Sverre; Hallerback, Maria Unenge; Evans, Sarah F.; Sathyanarayana, Sheela; Barrett, Emily S.; Nguyen, Ruby H. N. (2018). "Association of Prenatal Phthalate Exposure With Language Development in Early Childhood". JAMA Pediatrics. 172 (12): 1169–1176. doi:10.1001/jamapediatrics.2018.3115. PMC   6583016 . PMID   30383084.
  19. 1 2 Just, A. C., Whyatt, R. M., Perzanowski, M. S., Calafat, A. M., & Perera, F. P. (2012)Prenatal Exposure to Butylbenzyl Phthalate and Early Eczema in an Urban Cohort. Environmental Health Perspectives, 120(10), 1475–1480.
  20. ↑ Wittassek, Matthias; Angerer, Juergen; Kolossa-Gehring, Marike; Schäfer, Sebastian Daniel; Klockenbusch, Walter; Dobler, Lorenz; Günsel, Andreas K; Müller, Antje; Wiesmüller, Gerhard Andreas (2009). "Fetal exposure to phthalates – a pilot study". International Journal of Hygiene and Environmental Health. 212 (5): 492–498. Bibcode:2009IJHEH.212..492W. doi:10.1016/j.ijheh.2009.04.001. PMID   19423389.
  21. ↑ Hauser, Russ; Meeker, John D; Duty, Susan; Silva, Manori J; Calafat, Antonia M (2006). "Altered Semen Quality in Relation to Urinary Concentrations of Phthalate Monoester and Oxidative Metabolites". Epidemiology. 17 (6): 682–691. doi: 10.1097/01.ede.0000235996.89953.d7 . PMID   17003688. S2CID   13179021.
  22. 1 2 3 WHO IARC. (1999). Retrieved from http://monographs.iarc.fr/ENG/Monographs/vol73/mono73.pdf
  23. ↑ Martín, C; Casado, I; Pérez-Miguelsanz, J; López, Y; Maldonado, E; Maestro, C; Paradas, I; Martínez-Sanz, E; González, I; Martínez-Álvarez, C (2008). "Effect of Butyl Benzyl Phthalate on Early Postnatal Mortality in Rats". Toxicology Mechanisms and Methods. 18 (9): 759–762. doi:10.1080/15376510802399065. PMID   20020936. S2CID   31384950.
  24. 1 2 Ema, Makoto; Itami, Takafumi; Kawasaki, Hironoshin (1992). "Embryolethality and teratogenicity of butyl benzyl phthalate in rats". Journal of Applied Toxicology. 12 (3): 179–183. doi:10.1002/jat.2550120305. PMID   1629513. S2CID   23378037.
  25. 1 2 Nagao, Tetsuji; Ohta, Ryo; Marumo, Hideki; Shindo, Tomoko; Yoshimura, Shinsuke; Ono, Hiroshi (2000). "Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: A two-generation reproductive study". Reproductive Toxicology. 14 (6): 513–532. Bibcode:2000RepTx..14..513N. doi:10.1016/S0890-6238(00)00105-2. PMID   11099877.
  26. ↑ NTP. (1997). Effect of Dietary Restriction on Toxicology and Carcinogenesis Studies in F344/N Rats and B6C3F1 Mice. Retrieved from https://ntp.niehs.nih.gov/go/tr460abs
  27. ↑ Staples et al. 1997. Aquatic toxicity of eighteen phthalate esters. Environmental toxicology and chemistry 16 (5), 875-89
  28. ↑ Staples, Charles A; Peterson, Dennis R; Parkerton, Thomas F; Adams, William J (1997). "The environmental fate of phthalate esters: A literature review". Chemosphere. 35 (4): 667–749. Bibcode:1997Chmsp..35..667S. doi:10.1016/S0045-6535(97)00195-1.
  29. ↑ "OEHHA Adds Three Phthalates as Reproductive Toxicants to Prop 65 List". Archived from the original on 2013-07-03. Retrieved 2013-07-03.
  30. ↑ "OEHHA Adopts BBP MADL". Archived from the original on 2015-04-02. Retrieved 2013-07-03.
  31. ↑ Canada Gazette - Phthalates Regulations Archived 2010-11-25 at the Wayback Machine
  32. ↑ EVALUATION OF NEW SCIENTIFIC EVIDENCE CONCERNING THE RESTRICTIONS CONTAINED IN ANNEX XVII TO REGULATION (EC). [ebook] European Chemicals Agency, pp.2-12. Available at: https://echa.europa.eu/documents/10162/13641/bbp_echa_review_report_2010_6_en.pdf/4bf571c1-e168-4f10-a90c-b98e2de08916 [Accessed 18 Mar. 2018]
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