Dimethyl phthalate

Dimethyl phthalate is an organic compound with the molecular formula (C2H3O2)2C6H4. The methyl ester of phthalic acid is a colourless and oily liquid that is soluble in organic solvents.[4]

Dimethyl phthalate[1][2]
Names
Preferred IUPAC name
Dimethyl benzene-1,2-dicarboxylate
Other names
Dimethyl phthalate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.004.557
KEGG
UNII
  • 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
  • O=C(OC)c1ccccc1C(=O)OC
Properties
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)
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)
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

Dimethyl phthalate (DMP) is used in various laboratories and manufacturing companies for pharmaceutical and biotechnological research worldwide.[5] Presently, 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][6] Other uses of DMP include solid rocket propellants and plastics.[4][6]

The U.S Environmental Protection Agency has classifed Dimethyl phthalate as not classifiable for human carcinogenicity.[7][8] 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.[9]

Synthesis

Dimethyl phthalate is a man-made compound that is manufactured commercially in a closed system from phthalic anhydride. The compound is made via an esterification reaction. It starts with direct esterification with methanol catalysed by esterification catalysts such as titanium, zirconium and tin catalysts. Excess alcohols are removed from the DMP mixture via steam stripping or other distillation methods and eventually recycled. Concurrently, the DMP mixture is purified via vacuum distillation or activated charcoal. With current manufacturing processes, the purity of DMP may reach up to 99% or greater.[4][10]

Reactivity and mechanism of action

Dimethyl phthalate reacts with acids, generating heat along with alcohols and acids. It belongs to the reactive groups of esters that react vigorously with strong oxidizing acids causing a sufficient exothermic reaction to ignite the reaction products. Alkali metals and hydrides produce flammable hydrogen when mixed with esters.[11] The compound is used as a plasticizer for veterinary medicines, a substance that makes materials softer and more flexible by increasing its plasticity.[12] Among other chemicals, DMP is present in insect repellents and especially useful against ixodid ticks responsible for Lyme disease.[13] However, the exact mechanism that causes the anti-insectoid properties of DMP is not completely understood.

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.[14] Most specifically, cell membrane deformation and membrane channels misopening were observed, as well as altered gene expression responsible of energy metabolism.[15]

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.[16] 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.[17]

Route of exposure

Route of exposure to DMP is commonly from inhalation, oral and dermal contact with the compound. Occupational exposure to DMP may also be possible through inhalations of aerosols and dermal contact at workplaces where the compound is consistently produced.[4]

Side effects

Acute exposure to DMP via inhalation in humans and animals have shown to result in irritation to the eyes, nose and throat.[18] Although some research has shown the association between the susceptibility of the reproductive system and phthalates esters, most phthalates demonstrate low acute toxicity.[4][19]

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.[7][8][20] 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][19]

Efficacy

Dimethyl phthalate has shown promising and consistent results as an insect repellant, especially towards mosquitoes, flies and ticks. DMP has been shown to deter species of mosquitoes such as Anopheles stephensi, Culex pipeins and Ades aegypti.[21][22][23] A study showed a significant decrease in man-vector contact with the presence of DMP wristbands.[21] Another study observed a significant difference between the use of synthetic repellant and plant-based repellant against Anopheles stephensi mosquitoes. The results of DMP showed good repellency with an ED50 of 0.0076 mg/cm2 with a protection time of 9 hours on rabbits. As compared to the plant-based repellant, neem oil, with an ED50 of 0.159 mg/cm2 and a protection time of only 65 minutes on the same model organism.[22] Mosquitoes play a large role in the transmission of vector-borne diseases (Dengue, Yellow Fever and Chikungunia) as they act as vectors for viruses.[24] Thus, the ability of DMP to repel mosquitoes indicates the good efficacy of the compound.

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.[25]

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.[26]

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.[27]

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. link Additionally, pollution of DMP into the environment could also be harmful to micro-organisms and aquatic animals.[28]

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.[29] 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.[29] Hence, the release of DMP as waste into the environment should be more carefully considered.

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).
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