Dimethyl phthalate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Metabolism

Dimethyl phthalate (DMP) is rapidly cleaved to Monomethyl phthalate (MMP) in the intestinal mucosa by epithelial esterases. The monoester is more rapidly absorbed from the intestine than the corresponding diester [White et al.,1990].

DMP has been found to be completely hydrolyzed to the MMP and to some extend further hydrolyzed to phthalic acid in the receptor fluid of in vitro dermal penentration studies [Hotchkiss and Mint, 1994].

 

Percutaneous absorption and penentration

Several studies are available. In one study (Russian study, no translation available) the concentrations of DMP and its metabolite MMP in blood, tissues and organs after dermal application to rats were analyzed [Gleiberman et al., 1978]. In addition, the concentration in blood and urine was confirmed with human volunteers. However, the experimental details are not fully transparent, and the results are not representative for percutaneous penetration and absorption. The absorption of 14C-DMP in rats in vivo was determined to be approximately 38% as determined by cumulated urinary excretion for seven days after application [Elsisi et al., 1989].

 

In vitro data have been published, where 25.5% and 3.5% percutaneous absorption has been found for rat and human skin, respectively [Hotchkiss and Mint, 1994]. It was published recently, that the percutaneous absorption through rat skin in vitro was 26% without and 17% with occlusion after 72 hours. The percutaneous absorption through human skin in vitro was 4% with and without occlusion after 72 hours [Hotchkiss, 1998]. This species difference is well-known and has also been described for DMP [Hotchkiss and Mint, 1994; Scott et al., 1987]. Further in vitro studies [Scott et al., 1987] provided values of 2.5 to 4 μg/cm²/h for absorption of DMP through human epidermis and 40 to 50 μg/cm²/h through rat epidermis. Dermal absorption of DMP in rat was highly solvent dependent, with up to a 10-fold difference between different solvents. Ellison et al. [2020] determined similar values for human skin (dermatoed skin, whole epidermis, dermis and stratum corneum) ranging from 1.2 to 4.1 µg/cm²/h. However, it has to be mentioned that according to Olkowksa (2022), the values obtained in in vitro/ex vivo studies is highly dependent on the model used. The study author determined for example 35.8 µg/cm²/h for the Stat-M membrane model, in contrast to 1.4 µg/cm² for the human XenoSkin H model with DMP.

Following oral administration in rats, the primary metabolites for DMP in urine were the monoester monomethyl phthalate MMP (78%) with some free phthalic acid (14.4%) and unchanged DMP (8.1%) [Albro & Moore, 1974]. Methanol and formaldehyde have been reported as in vivo and in vitro metabolites of DMP [Kozumbo & Rubin, 1991; Surina et al, 1984].

 

Of note, DMP was highly bioaccessible (>75%) from dust via artificial lung fluids [Kademoglou et al., 2018].

 

Conclusions

DMP is absorbed via the gastrointestinal tract and via skin. In rats, 6% per day of dermally applied DMP was recovered in urine and faeces over 7 days. In vitro, human epidermis was an order of magnitude less permeable to DMP than rat epidermis. Following absorption, DMP is distributed to multiple organs but rapidly cleared, with no accumulation.

Following oral administration, the main DMP metabolites were the monoester MMP (78%), with free phthalic acid and unchanged DMP comprising the remainder of the eliminated dose. Methanol and formaldehyde have also been identified as metabolites in vivo and in vitro.