Absorption, Distribution and Excretion
Following oral administration of 14C dimethyl phthalate to rats or mice, radioactivity was detected in blood and various tissues. Peak radioactivity was reached within 1 hour. The highest radioactivity was observed in the kidneys, followed by the liver, fat, and spleen. After 24 hours, 91% of the administered dose was excreted in the urine and 4.1% in the feces. A series of phthalate esters, including dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and di(2-ethylhexyl) phthalate, were subjected to transdermal absorption assays using human and rat epidermal membranes mounted in a glass diffusion cell. These esters were applied directly to the epidermal membrane. After application, each phthalate exhibited a hysteresis phase followed by a linear absorption phase. For all four phthalates, human skin permeability was lower than that in rat skin. Larger molecular weights appear to correlate with longer hysteresis times, but this relationship is not always valid. Phthalate esters exhibit water solubility ranging up to 300 times and a wide range of lipophilicity. Skin permeability increases slightly upon contact with the human epidermis. Post-exposure, epidermal membrane permeability undergoes relatively significant changes. This study investigated the absorption of a range of phthalates on rat skin. The phthalates tested included: dimethyl phthalate, diethyl phthalate, dibutyl phthalate, diisobutyl phthalate, dihexyl phthalate, di(2-ethylhexyl) phthalate, diisodecyl phthalate, and benzylbutyl phthalate. A 1.3 cm diameter skin patch was taken from the back of male F344 rats, shaved, and 14(C) phthalate was applied at a dose of 157 μmol/kg. The applied area was then covered with a perforated cap. Rats were restrained and housed in metabolic cages for 7 days to collect urine and feces. Urine and feces were collected every 24 hours, and the amount of 14(C) excreted was used as an indicator of transdermal absorption. At 24 hours, diethyl phthalate (DIP) had the highest excretion rate (26%). The amount of 14(C) excreted in the first 24 hours decreased significantly with increasing alkyl side chain length. The highest percentage of cumulative excreted dose over 7 days was observed for DEP, DIB, and DIB, approximately 50-60% of the applied 14(C) dose. The absorption rates of DEP, DIB, and DIB were between these two (20-40%). Except for DIB, the primary route of excretion for all phthalate esters was urine. DIB had extremely low absorption and was almost entirely excreted in urine. Seven days later, the residual dose percentage of each phthalate in the body was extremely low, and no specific tissue distribution was observed. Most of the unexcreted dose remained at the administration site. These data suggest that the structure of the phthalates determines the extent of their transdermal absorption. Diethyl phthalate (DMP) had the highest absorption rate, which subsequently decreased significantly with increasing alkyl side chain length. DMP is readily absorbed from the skin, intestine, peritoneum, and lungs. For more complete data on the absorption, distribution, and excretion of the six dimethyl phthalates, please visit the HSDB record page. Metabolites/Metabolites: Intestinal extracts from humans, ferrets, and baboons, as well as liver extracts from the latter two animals, can break down dimethyl phthalate into monoesters. In vitro studies on the metabolism of dimethyl phthalate, dibutyl phthalate, di-n-octyl phthalate, and diethyl phthalate in rat liver and kidney homogenates showed that the lower the molecular weight of the phthalate, the faster the metabolic rate. Compared with liver homogenate, rat kidney homogenate showed a relatively slower degradation rate of esters. After a single oral gavage of 120 mg of dimethyl phthalate to rats via gastric tube, 44.6% of dimethyl phthalate was detected in the urine, of which 77.5% was monomethyl phthalate, 14.4% was phthalic acid, and 8.1% was intact dimethyl phthalate. …In host-mediated mutagenesis experiments, rats were intraperitoneally injected with dimethyl phthalate (DMP) (2 g/kg body weight); 24-hour urine was collected, and… phthalic acid-containing derivatives were extracted and analyzed. The extracted urine contained phthalic acid equivalent to 1.96 mg/mL of urine. Over 97% of the phthalic acid-containing derivatives in the extracted urine were non-mutagenic metabolites of DMP—methyl phthalate (MMP). In vitro experiments showed that rat liver homogenate hydrolyzed 93% of carbonyl-labeled (14)C-DMP (7.7 mM) to MMP within 2 hours, binding 0.07 nmol of (14)C phthalate/mg liver macromolecule. In contrast, rat epidermal homogenate metabolized only 5% of carbonyl-labeled (14)C-DMP, but its binding level was 38 times higher (2.66 nmol/mg macromolecule), and no binding to nucleic acids was detected. Compared to the skin and plasma, the liver exhibited a 5-fold higher DMP monoesterase activity (1240 nmol/hr/mg protein), and a 67% inhibition of this enzyme activity resulted in a 4.4-fold increase in the number of phthalate-bound macromolecules in the liver (0.31 nmol vs. 0.07 nmol carbonyl-labeled (14)C-DMP/mg macromolecule). In addition to MMP, DMP metabolism in the liver also produces formaldehyde. When ethanol was used to inhibit the oxidation of DMP-derived methanol from liver homogenate, formaldehyde accumulation was reduced by 74%, and the binding of methyl-labeled (14)C-DMP to nucleic acids and macromolecules was reduced by 71% and 73%, respectively. (Unlike carbonyl-labeled (14)C-DMP, methyl-labeled (14)C-DMP hydrolyzes to (14)C-labeled methanol.) These results indicate that DMP diesters…can bind to other macromolecules in the skin and liver, in addition to nucleic acids. Although DMP is rapidly metabolized in the liver to monoesters (MMPs) and methanol, thus preventing elevated phthalate binding levels and DMP-induced bacterial mutations, it also oxidizes DMP-derived methanol to formaldehyde, a metabolite capable of binding to macromolecules, including nucleic acids. For more complete data on the metabolism/metabolites of dimethyl phthalates (12 in total), please visit the HSDB record page. Phthalate esters are first hydrolyzed to monoester derivatives. Once formed, these derivatives can be further hydrolyzed in the body to phthalic acid or conjugated with glucuronic acid, both of which are excreted. The terminal or penultimate carbon atom of the monoester can also be oxidized to an alcohol, which can be excreted directly or first oxidized to an aldehyde, ketone, or carboxylic acid. Monoesters and their oxidized metabolites are excreted in urine and feces. (A2884)

Toxicity Summary
Identification and Uses: Dimethyl phthalate (DMP) is a pale yellow or colorless oily liquid (solid below 42°F) with a slightly aromatic odor. It is used as a plasticizer in nitrocellulose and cellulose acetate resins, and as a component in solid rocket propellants, varnishes, plastics, rubber, coatings, safety glass, and molding powders. In the past, it has been used as a fly repellent and leech repellent for horses and cattle. DMP is not currently registered for use in the United States, but approved pesticide uses may change periodically; therefore, it is essential to consult federal, state, and local authorities for current approved uses. Human Exposure and Toxicity: In humans, dimethyl phthalate can cause skin irritation and, in one individual, induce anaphylaxis. Repeated inhalation of its vapors can irritate the nasal cavity and upper respiratory tract. Ingestion of dimethyl phthalate (DMP) may cause stomach irritation, dizziness, and coma. In a fatal case of suicidal ingestion of a mixture containing dimethyl phthalate and ketone peroxides, the primary symptoms of poisoning were marked esophagitis, gastritis, and bleeding. After 18 hours of in vitro culture containing 0.4 mM DMP, the in vitro mortality rate of human sperm decreased by 25%. DMP did not cause chromosomal damage in human leukocytes. DMP is not a known human carcinogen. Animal studies: Repeated application of DMP to the skin of mice caused irritation and ulceration, but produced only mild skin and ocular toxicity in rabbits. Acute oral and dermal toxicity was low in several animals. Oral studies in rats showed that repeated exposure to DMP may lead to kidney damage and mild liver damage. Repeated skin contact with DMP in rabbits resulted in kidney and liver damage. Inhalation of DMP at a concentration of 250 ppm caused severe mucosal irritation in cats; at a concentration of 1250 ppm, animals exhibited lethargy. In mice, inhalation of 0.7–1.8 mg/m³ DMP (4 hours daily) for 4 months resulted in changes in respiratory rate, neurological function, liver and kidney function, and blood morphology. Feeding rats with a diet containing 2% dimethyl phthalate for one week significantly reduced testosterone levels in the testes and serum, as well as serum dihydrotestosterone levels. Offspring of mice and rats administered DMP orally or dermatologically developed normally, while intraperitoneal injection of DMP in pregnant rats resulted in fetal death and malformations. Repeated application of DMP to the skin of mice did not increase the tumorigenicity of known skin carcinogens. Mutagenic activity of DMP was observed in Salmonella typhimurium (Ames test). Signs of chromosomal damage appeared in hepatocytes of rats with repeated dermal DMP application, but this was not observed in bone marrow cells of mice with a single DMP injection. In cultured Chinese hamster ovary cells, DMP induced sister chromatid exchange only upon metabolic activation. DMP did not induce chromosomal aberrations in cultured Chinese hamster ovary cells regardless of metabolic activation. Therefore, DMP is mutagenic only after metabolism in certain in vitro studies. This may be due to the formation of active substances such as formaldehyde. Since DMP is not mutagenic in vivo, any active metabolites appear to be rapidly detoxified. Ecotoxicity study: 100 ppm DMP showed acute toxicity to larvae of Palaemonetes pugio (grass shrimp). A concentration of 100 ppm DMP significantly prolonged the time required for larval development to the first larval stage. This study investigated the bioavailability of phthalate compounds, including dimethyl phthalate (DMP), in earthworms (Eisenia fetida). Earthworms were exposed to two artificially contaminated farmland and forest soils. The results showed that phthalates were not detected in the earthworms. Phthalate compounds are endocrine disruptors. They reduce testosterone production in the fetal testes and inhibit the expression of steroid-producing genes by reducing mRNA expression. Some phthalate compounds have also been shown to reduce the expression of insulin-like peptide-3 (insl3). insl3 is an important hormone secreted by interstitial cells of the testes and is crucial for the development of the gubernaculum testis. Animal studies have shown that these effects can disrupt reproductive development and may lead to various malformations in affected offspring. (A2883)

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Toxicity Data
LCLo (cat) = 9,630 mg/m3/6H
LD50: 6800 mg/kg (oral, rat) (T13)
LD50: 3375 mg/kg (intraperitoneal, rat) (T13)
LD50: 38000 mg/kg (dermal, rat) (L1332)
LD50: 324 mg/kg (intravenous, rat) (L1332)

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Interactions
……Mice were sensitized percutaneously with fluorescein isothiocyanate (FITC) dissolved in acetone containing phthalates. Sensitization was assessed by ear swelling after FITC stimulation. Drained lymph node cells were collected 24 hours after skin sensitization, and FITC fluorescence was detected by flow cytometry. FITC-positive cells were identified by three-color flow cytometry using anti-CD11c and anti-CD11b antibodies. ... When mice were sensitized with FITC in acetone solution containing dibutyl phthalate (DBP) or di-n-propyl phthalate (DPP), a significantly enhanced ear swelling response was observed. Dimethyl phthalate (DMP) and diethyl phthalate (DEP) had weaker effects, but still produced some enhancement. ...

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Non-human toxicity values
Oral LD50 in rats: 6800 mg/kg
Oral LD50 in rats: 2860 mg/kg
Intraperitoneal LD50 in rats: 3375 mg/kg
Dermal LD50 in rats: 38000 mg/kg
For more complete non-human toxicity data on dimethyl phthalate (out of 13), please visit the HSDB record page.

[1]. Impacts of dimethyl phthalate on the bacterial community and functions in black soils. Front Microbiol. 2015 May 5;6:405.

Dimethyl phthalate (DMT) is a water-white liquid with no noticeable odor. It is denser than water, insoluble in water, and therefore sinks. Its flash point is 300°F (149°C). Contact with eyes may cause severe irritation, and direct skin contact may cause mild irritation. It is used in the manufacture of a variety of products, including plastics, insect repellents, safety glass, and varnish coatings. DMT is a phthalate, diester, and methyl phthalate. DMT has a wide range of uses, including in solid rocket propellants, plastics, and insect repellents. Acute (short-term) exposure to DMT via inhalation in humans and animals can cause irritation to the eyes, nose, and throat. There is currently no information on the chronic (long-term), reproductive, developmental, or carcinogenic effects of DMT in humans. Animal studies suggest that long-term oral ingestion of this chemical may have mild effects on growth and kidneys. The U.S. Environmental Protection Agency (EPA) has classified DMT as a Group D substance, meaning its carcinogenicity in humans cannot be determined. Dimethyl phthalate (DMT) has been reported to be found in scallions (Allium ampeloprasum), the Canadian larva (Cryptotaenia canadensis), and other organisms with relevant data. DMT is a phthalate ester. Phthalate esters are esters of phthalic acid, primarily used as plasticizers, mainly for softening polyvinyl chloride (PVC). They are found in a wide variety of products, including adhesives, building materials, personal care products, detergents and surfactants, packaging materials, children's toys, paints, pharmaceuticals, food, and textiles. Phthalate esters have endocrine-disrupting effects and are therefore harmful. Due to these health concerns, the United States and the European Union are phasing out phthalates from many products. (L1903)

C10H10O4

194.19

194.057

131-11-3

Dimethyl phthalate (Ring-d4);93951-89-4;Dimethyl phthalate-d6;85448-30-2

8554

Colorless to light yellow liquid

1.2±0.1 g/cm3

282.7±8.0 °C at 760 mmHg

2 °C(lit.)

146.1±0.0 °C

0.0±0.6 mmHg at 25°C

1.515

1.64

0

4

4

14

200

0

O=C(OC)C1=CC=CC=C1C(OC)=O

NIQCNGHVCWTJSM-UHFFFAOYSA-N

InChI=1S/C10H10O4/c1-13-9(11)7-5-3-4-6-8(7)10(12)14-2/h3-6H,1-2H3

dimethyl benzene-1,2-dicarboxylate

NSC-15398; NSC 15398; Dimethyl phthalate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~514.99 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.87 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (12.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)