Dimethyl phthalate

Dimethyl phthalate is an organic compound and phthalate ester. it is a colourless and oily liquid that is soluble in organic solvents,[4] but which is only poorly soluble in water (~4 g/L).

Dimethyl phthalate[1][2]
Names
Preferred IUPAC name
Dimethyl benzene-1,2-dicarboxylate
Other names
Dimethyl phthalate
Identifiers
CAS Number
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.004.557
KEGG
PubChem CID
UNII
InChI
  • InChI=1S/C10H10O4/c1-13-9(11)7-5-3-4-6-8(7)10(12)14-2/h3-6H,1-2H3 Y
    Key: NIQCNGHVCWTJSM-UHFFFAOYSA-N Y
  • InChI=1/C10H10O4/c1-13-9(11)7-5-3-4-6-8(7)10(12)14-2/h3-6H,1-2H3
    Key: NIQCNGHVCWTJSM-UHFFFAOYAF
SMILES
  • O=C(OC)c1ccccc1C(=O)OC
Properties
Chemical formula
 C10H10O4
Molar mass 194.184 g/mol
Appearance Colorless oily liquid
Odor slight aromatic odor[2]
Density 1.19 g/cm3
Melting point 2 °C (36 °F; 275 K)
Boiling point 283 to 284 °C (541 to 543 °F; 556 to 557 K)
Solubility in water
 0.4% (20°C)[2]
Vapor pressure 0.01 mmHg (20°C)[2]
Pharmacology
P03BX02 (WHO) QP53GX02 (WHO)
Hazards
Flash point 146 °C (295 °F; 419 K)
Autoignition
temperature
 460 °C (860 °F; 733 K)
Explosive limits 0.9%-?[2]
Lethal dose or concentration (LD, LC):
6900 mg/kg (rat, oral)
1000 mg/kg (rabbit, oral)
2400 mg/kg (guinea pig, oral)
6800 mg/kg (rat, oral)
6800 mg/kg (mouse, oral)
4400 mg/kg (rabbit, oral)
2400 mg/kg (guinea pig, oral)[3]
9630 mg/m3[3]
NIOSH (US health exposure limits):
PEL (Permissible)
 TWA 5 mg/m3[2]
REL (Recommended)
 TWA 5 mg/m3[2]
IDLH (Immediate danger)
 2000 mg/m3[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Y verify (what is YN ?)
Infobox references

It is used in a variety of products and is most commonly used as insect repellent such as ectoparasiticide for mosquitoes and flies for animal livestock.[4] The short-chain or low molecular weight phthalate is also frequently used in consumer products such as cosmetics, ink, soap, household cleaning supplies, etc.[5] Other uses of DMP include solid rocket propellants and plastics.[4][5]

The U.S Environmental Protection Agency has classified Dimethyl phthalate as not classifiable for human carcinogenicity.[6][7] Its oral LD50 is 4390 to 8200 mg/kg bw/d in rats and the dermal LD50 is 38000 mg/kg bw in rats and more than 4800 mg/kg bw in guinea pigs.[8]

Synthesis

Dimethyl phthalate is manufactured commercially via the esterification of phthalic anhydride with methanol. The reaction can be catalysed by a strong acid, such as sulfuric acid; various lewis acids may be used as an alterative, including complexes of titanium, zirconium or tin. Excess methanol is used to ensure complete conversion, with the remainder removed by distillation at the end.[4][9]

Applications

Unlike most other phthalate esters, dimethyl phthalate is rarely used as a plasticizer for PVC. It is considered too volatile and causes excessive fuming during PVC processing.[10] It is a good plasticizer for cellulose-esters, including cellulose acetate, cellulose acetate butyrate and cellulose propionate compositions. Historically, this led to it being present in nail polish and some artificial nails but it is not commonly used today.[11] It is used as a plasticizer for cellulose acetate phthalate, which is used to make enteric coatings for medicines.[12] Other cosmetic uses include as a fixative for perfumes, although it is not as commonly used as DEP.[13] Dimethyl phthalate is able to dissolve nitrocellulose which made it historically important in some automotive coatings and vanishes.

Insect repellent

DMP can be used as an insect repellent and is especially useful against ixodid ticks responsible for Lyme disease.[14] DMP has been shown to deter species of mosquitoes such as Anopheles stephensi, Culex pipeins and Ades aegypti.[15][16][17]

Metabolism/Biotransformation

DMP administered orally in rats largely undergoes phase I biotransformation to monomethyl phthalate (MMP) via hydrolysis in the liver and intestinal mucosa. MMP may also be further hydrolysed to phthalic acid.[18] However, low molecular weight phthalates such as MMP are primarily excreted as monoesters and do not undergo phase II biotransformation processes such as hydroxylation and oxidation unlike the well-known banned molecule DEHP.[19]

Human safety

Acute exposure to DMP via inhalation in humans and animals have shown to result in irritation to the eyes, nose and throat.[20] Although some research has shown the association between the susceptibility of the reproductive system and phthalates esters, most phthalates demonstrate low acute toxicity.[4][21]

Unfortunately, the chronic (long term), reproductive effects and carcinogenicity of DMP on humans and animals have yet to be fully established as compared to other phthalate esters.[6][7][22] This is due to insufficient animal evidence and inadequate lifetime-exposure carcinogenicity studies available. However, DMP does appear to have less potential towards inducing health hazards than other phthalates, such as DEHP and BBP.[4][21]

Animal toxicity

Studies have shown that DMP is readily absorbed in the gastrointestinal tract of rats. After an orally administered dose of 0.1mL of DMP, about 77% of monomethyl phthalate and 8% of DMP have been detected in urine collected for 24 hours from male rats. Acute oral toxicity results in an LD50 of 8,2, 5,2, 2,9, 10,1 and 8,6 mg/kg for rats, rabbits, guinea pigs, chicks, and mice respectively. Another study on Sprague-Dawley albino rats resulted in a lower LD50 of 4,39 mg/kg in females and 5,12 mg/kg in males. Treatment was applied and for dead subjects, necropsy revealed toxic effects in the lungs, stomach and intestines of rats. Based on this animal data, DMP does not fit the definition of ''acute toxic'' under FHSA via oral exposure.[23]

Hematoxicity

At high doses (1000 mg/kg), DMP may cause red blood cells (RBCs) to lose their oxygen-carrying function. In both in vitro and in vivo rat studies, DMP-incubated red blood cells released iron. Iron is the site of oxygen binding for hemoglobin, without it, hemoglobin is unable to bind to oxygen and transport it to the rest of the body. Release of iron from RBCs was not found in RBCs not incubated with DMP, nor at low and medium doses of DMP. One mechanism of iron release is the oxidative stress-induced on RBCs by DMP.[24]

A separate study found that the oxidative stress induced by DMP also decreased the immune functions of erythrocytes. The oxidative stress damages the structure and function of erythrocytes, in particular RBC-complement 3b (C3b) receptors.[25]

Hepatotoxicity

Animal studies on oral exposure of DMP in rats have established hepatotoxic effects including increased liver weight, elevated alkaline phosphatase activity and reduced cholesterol and lipid levels.[4] Increased liver weight was identified in rats exposed to DMP concentrations of approximately 1,860 mg/kg-day; heightened alkaline phosphatase activity (indicating liver damage) followed prolonged dosage of 500 mg/kg–day; lowered cholesterol and lipid levels were observed after exposure to 107 mg/kg-day.

Environmental toxicity

Environmental contamination by phthalates, inclusive of DMP, has been a pressing issue for human and marine health. DMP is readily released to the environment could potentially pose harmful risks of exposure on humans. Additionally, pollution of DMP into the environment could also be harmful to micro-organisms and aquatic animals.[26]

Toxic effects on bacteria

A study on the environmental contamination of DMP has a direct influence on the cell function of Pseudomonas fluroescens (P. fluorescens), such as inhibition of growth, reduced glucose utilisation, etc. Results from the study suggest the presence of alterations in gene expressions that are involved in energy metabolism such as ATP-binding cassette transporters.[27] Additionally, inhibition of the Cori cycle and glycolysis pathway by DMP were also observed in the bacteria. P. fluorescens, a Plant Growth Promoting Rhizobacterium (PGPR), is an important bacteria found in soil, leaves and water that produces metabolites that allow plants to resist biotic and abiotic stresses.[27] Hence, the release of DMP as waste into the environment should be more carefully considered.

Another study shows the ability of DMP to inhibit the growth and glucose utilization of Pseudomonas fluorescens, a species that can cause bacteremia in humans.[28] Most specifically, cell membrane deformation and membrane channels misopening were observed, as well as altered gene expression responsible of energy metabolism.[29]

Aquatic toxicity

The toxicity of DMP on adult zebrafish (Danio rerio) was examined and showed oxidative damage after high concentrations of exposure. There was also found that antioxidant enzymes can be used as biochemical markers to identify the toxicant to be DMP.[30] The LC50 after 96h of exposure was 45.8 mg/L, with 100% of mortality in the 200 mg/L exposure group. After 96h of exposure at high concentrations the activity levels of the primary antioxidant enzymes catalase, superoxide dismutase, and glutathione transferase activities were significantly reduced. This resulted in reduction of gene expression of these enzymes. Antioxidant enzymes act as defenders of cells from oxidant damage from contaminants present as free radicals that can cause enzyme inactivation, DNA and cholesterol damage and peroxidation of unsaturated fats in the cell membrane. The degree of lipid peroxidation in animals can be measured by following the trend in concentration of malondialdehyde, that is a product of lipid peroxidation. That is an indicator of DMP exposure.[30]

References
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  2. NIOSH Pocket Guide to Chemical Hazards. "#0228". National Institute for Occupational Safety and Health (NIOSH).
  3. "Dimethylphthalate". Immediately Dangerous to Life or Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH).
  4. Carlson KR, Patton LE. Toxicity Review for Dimethyl Phthalate (DMP, CASRN 131-11-3) (PDF) (Report). U.S Consumer Product Safety Commission.
  5. Schettler T (February 2006). "Human exposure to phthalates via consumer products". International Journal of Andrology. 29 (1): 134–139, discussion 181–185. doi:10.1111/j.1365-2605.2005.00567.x. PMID 16466533.
  6. Phillips L (June 2015). "EPA's Exposure Assessment Toolbox (EPA-Expo-Box)". Journal of Environmental Informatics. 25 (2): 81–84. doi:10.3808/jei.201400269. ISSN 1726-2135. S2CID 113872276.
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  9. US 5534652, Jones L, Daniels PH, Krauskopf LG, Rigopoulos KR, "Preparation of plasticizer esters from phthalic anhydride residue", issued 1996-07-09
  10. Verlag, Carl Hanser (2009). Plastics additives handbook (6. ed.). Munich. p. 490. ISBN 978-3-446-40801-2.
  11. Young, AS; Allen, JG; Kim, UJ; Seller, S; Webster, TF; Kannan, K; Ceballos, DM (6 November 2018). "Phthalate and Organophosphate Plasticizers in Nail Polish: Evaluation of Labels and Ingredients". Environmental Science & Technology. 52 (21): 12841–12850. Bibcode:2018EnST...5212841Y. doi:10.1021/acs.est.8b04495. PMC 6222550. PMID 30302996.
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  16. Nathan, Sengottayan Senthil; Kalaivani, Kandaswamy; Murugan, Kadarkarai (October 2005). "Effects of neem limonoids on the malaria vector Anopheles stephensi Liston (Diptera: Culicidae)". Acta Tropica. 96 (1): 47–55. doi:10.1016/j.actatropica.2005.07.002. ISSN 0001-706X. PMID 16112073.
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  18. https://www.frontiersin.org/files/Articles/548585/fpubh-08-00366-HTML/image_m/fpubh-08-00366-t001.jpg. {{cite web}}: Missing or empty |title= (help)
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  22. Gray, L. E.; Ostby, J.; Furr, J.; Price, M.; Veeramachaneni, D. N.; Parks, L. (December 2000). "Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat". Toxicological Sciences. 58 (2): 350–365. doi:10.1093/toxsci/58.2.350. ISSN 1096-6080. PMID 11099647.
  23. R. Carlson E. Patton, Kent Leslie (October 30, 2010). "Toxicity Review of Dimethyl phthalate" (PDF). United states consumer product safety commission. Archived (PDF) from the original on 2017-01-31. Retrieved March 17, 2022.
  24. Chi, Zhenxing; Liu, Jia; Tan, Songwen; Lin, Hongwei; Wu, Weilin; Li, Weiguo (2021-01-01). "Revealing the toxicity of dimethyl phthalate (DMP) to the oxygen-carrying function of red blood cells (RBCs): The iron release mechanism". Chemosphere. 263: 128017. Bibcode:2021Chmsp.263l8017C. doi:10.1016/j.chemosphere.2020.128017. ISSN 0045-6535. PMID 32841881. S2CID 221325980.
  25. Li, Shixuan; Chi, Zhenxing; Li, Weiguo (2019-10-01). "Invitro toxicity of dimethyl phthalate to human erythrocytes: From the aspects of antioxidant and immune functions". Environmental Pollution. 253: 239–245. doi:10.1016/j.envpol.2019.07.014. ISSN 0269-7491. PMID 31319240. S2CID 197664449.
  26. Prasad, Bablu (2021-04-01). "Phthalate pollution: environmental fate and cumulative human exposure index using the multivariate analysis approach". Environmental Science: Processes & Impacts. 23 (3): 389–399. doi:10.1039/D0EM00396D. ISSN 2050-7895. PMID 33566875. S2CID 231883186.
  27. Wang, Zhigang; Wang, Chunlong; You, Yimin; Xu, Weihui; Lv, Zhihang; Liu, Zeping; Chen, Wenjing; Shi, Yiran; Wang, Junhe (2019-01-15). "Response of Pseudomonas fluorescens to dimethyl phthalate". Ecotoxicology and Environmental Safety. 167: 36–43. doi:10.1016/j.ecoenv.2018.09.078. ISSN 0147-6513. PMID 30292974. S2CID 52947405.
  28. Scales, Brittan S.; Dickson, Robert P.; LiPuma, John J.; Huffnagle, Gary B. (October 2014). "Microbiology, Genomics, and Clinical Significance of the Pseudomonas fluorescens Species Complex, an Unappreciated Colonizer of Humans". Clinical Microbiology Reviews. 27 (4): 927–948. doi:10.1128/CMR.00044-14. ISSN 0893-8512. PMC 4187640. PMID 25278578.
  29. Huang, Ling; Zhu, Xunzhi; Zhou, Shixing; Cheng, Zhenrui; Shi, Kai; Zhang, Chi; Shao, Hua (July 2021). "Phthalic Acid Esters: Natural Sources and Biological Activities". Toxins. 13 (7): 495. doi:10.3390/toxins13070495. ISSN 2072-6651. PMC 8310026. PMID 34357967.
  30. Cong, Bailin; Liu, Cong; Wang, Lujie; Chai, Yingmei (April 2020). "The Impact on Antioxidant Enzyme Activity and Related Gene Expression Following Adult Zebrafish (Danio rerio) Exposure to Dimethyl Phthalate". Animals. 10 (4): 717. doi:10.3390/ani10040717. ISSN 2076-2615. PMC 7222705. PMID 32325949.
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