Bis[C5-(linear and branched)-alkyl] benzene-1,4-dicarboxylate

Endpoint summary

Description of key information

No toxicokinetic studies are available. The toxicokinetics of DiPT was assessed based on physico-chemical data, the toxicological profile and available metabolism studies from the literature.

The molecular weight, water solubility, octanol/water partition coefficient and QSAR predictions favours oral and inhalative absorption, whereas dermal absorption is considered to be very low. DiPT may be distributed throughout the body in a moderate way. It is assumed that DiPT does not build reactive metabolites. It is assumed that DiPT is hydrolyzed by esterase enzymes to TPA and the respective alcohol moieties (Ball et al., 2012). Furthermore, rapid hydrolysis in vitro of comparable diesters like di-n-butyl terephthalate and 2-ethylhexyl methyl terephthalate (Batelle, 2007) indicates limited systemic availability of DiPT as parent ester.

Additional information

Toxicokinetic Statement of Di-(iso)-pentyl-terephthalate (DiPT)

 

General

DiPT (also named Di-iso-pentyl terephthalate)is a di-ester ofterephthalic acid (TPA) and the reaction mass of 2-methylbutan-1-ol and pentan-1-ol (EC No. 903-139-3), also referred to as mixture of branched and linear pentanols.

No experimental data on absorption, distribution, metabolism and excretion of DiPT are available.

According to REACH, the human health hazard assessment shall consider the toxicokinetic profile (Annex I). However, generation of new data is not required as the assessment of the toxicokinetic behaviour of the substance should be performed to the extent that can be derived from the relevant available information (REACH Annex VIII, 8.8.1).

Qualitative information on toxicokinetic behaviour can be derived taking into account the information on the chemical properties of the compound as well as data obtained in a basic data set. Furthermore, the behavior of the formed metabolites within the body should be taken in account.

 

Absorption

The observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information. Acute oral and dermal toxicity, Skin sensitisation and irritation as well as subacute oral toxicity was not observed with DiPT. No information on inhalatory toxicity is available. Thus, data from toxicity studies do not give any indication for the extend of absorption.

To be absorbed, the substance has to cross biological membranes, either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, and water solubility. In general, low molecular weight (MW ≤ 500) and moderate lipophilicity (log P values of - 1 to + 4) are favourable for membrane penetration and thus absorption. The molecular weight of DiPT is relatively moderate with 306 g/mol, favouring oral absorption of the compound; however, the substance is highly lipophilic (log of 6.6) and water solubility is very low (79 µg/L) indicating that absorption by passive diffusion may be limited. For highly lipophilic substances uptake by micellular solubilisation may be of particular importance, particularly for those that are poorly soluble in water (1 mg/L or less) (ECHA Guidance R.7c, Chapter R7.12.2.1).

Rarely, exogenous compounds (e.g. similar to a nutrient) may be taken up via a carrier mediated or active transport mechanism. However, prediction in this direction is not generally possible. Active transport (efflux) mechanisms also exist to remove exogenous substances from gastrointestinal epithelial cells thereby limiting entry into the systemic circulation. From physicochemical data, identification of substances ready for efflux is not possible.

Dermal uptake is expected to be moderate at this molecular weight level (< 100: dermal uptake high; > 500: no dermal uptake). However, for dermal uptake, sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. Therefore, at the water solubility level of below 1 mg/L, dermal uptake is likely to be low. The log P of 6.6 supports this estimation; at values above 6 the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. As a conclusion, based on the high log P outside the range of - 1 to 4, a default value of 10% skin absorption can be used for risk assessment (ECHA Guidance R.7c, Chapter R7.12.2.1).

For respiratory uptake it can be considered that generally liquids would readily diffuse/dissolve into the mucus lining. Thereby, lipophilic substances with moderate log P values (between - 1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. However, any lipophilic compound may be taken up by micellular solubilisation. This mechanism may be of particular importance for highly lipophilic compounds (log P > 4) like DiPT, which are poorly soluble in water (1 mg/L or less) and that would otherwise be poorly absorbed (ECHA Guidance R.7c, Chapter R7.12.2.1).

Thus, in the following QSAR predictions and reference to other well-studied substances were taken into account. QSAR predictions obtained from the Danish (Q)SAR database (2009) for one of the isomers (Di-n-pentyl-terephthalate) revealed the gastrointestinal absorption to be about 100% for a 1 mg dose of DiPT, whereas dermal uptake is predicted to be very low (0.000146 mg/cm2/event).

For the very well studied orthophthalates DINP (Diisononylphthalate) and DIDP (Diisodecylphthalate) the following absorption rates were used for the derivation of DNELs (ECHA 2013): oral 50% in rats and 100% in humans, inhalation 75% in humans, dermal 4% in rats and humans. DiPT is not an orthophthalate but belongs to the group of terephthalates, however, its molecule characteristics in terms of structure complexity, lipophilicity and water solubility appear comparable.

It can be summarized that the moderate molecular weight of DiPT of 306 g/mol would allow direct absorption through membranes, however, passive diffusion is most probably very limited by the high lipophilicity and the low water solubility. It this therefore assumed that oral and respiratory uptake might roughly be in the same moderate range; whereas dermal absorption is considered to be very low. This is in line with the absorption values that were used by the ECHA for the derivation of DNELS for DINP and DIDP, thus those values are also used for the risk assessment and the derivation of DNELS for DiPT.

 

Distribution

Some information or indication on the distribution of the compound in the body might be derived from the available physico-chemical and toxicological data. Once a substance has entered the systemic circulation, its distribution pattern is likely to be similar for all administration routes. However, first pass effects after oral exposure influence the distribution pattern and distribution of metabolites is presumably different to that of the parent compound.

The smaller a molecule, the wider is its distribution throughout the body. The molecular weight of 306 g/mol of DiPT indicates a moderate distribution in the body. Through its high lipophilie (log P = 6.6), DiPT is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissue.

The results of the toxicity studies identify no target organ toxicity. In addition, no effects on spermatogenesis were observed in the repeated dose toxicity study, thus no conclusion regarding blood-testes barrier penetration can be drawn.

The QSAR predictions obtained from the Danish (Q)SAR database (2009) for one of the isomers (Di-n-pentyl-terephthalate) calculates a Log brain/blood partition coefficient of 0.656. That means that DiPT will be able to cross the blood-brain barrier in moderate way and reach the central nervous system (CNS).

 

Bioaccumulation

Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, highly lipophilic (log P > 4) compounds tend to have longer biological half-lives. Thus, they potentially accumulate within the body in adipose tissue, especially after frequent exposure (e.g. at daily work) and the body burden can be maintained for long periods of time. After the stop of exposure, the substance will be gradually eliminated dependent on its half-life. During mobilization of fat reserves, e.g. under stress, during fasting or lactation, release of the substance into the serum or breast milk is likely, where suddenly high substance levels may be reached.

After dermal exposure, highly lipophilic (log P between 4 and 6) compounds may persist in the stratum corneum, as systemic absorbance is hindered.

With the log P value of 6.6, DiPT is highly lipophilic and thus will tend to concentrate in adipose tissue during workplace exposure.

 

Metabolism

Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. It is even more difficult to predict the extent of metabolism along different pathways and species differences possibly existing.

Evidence for differences in toxic potencies due to metabolic changes can be derived for instance from in vitro genotoxicity tests conducted with or without metabolic activation. Regarding the in vitro genotoxicity of DiPT, all studies in mammalian cells regarding gene mutation (OECD 490), chromosome aberration (OECD 473) and micronucleus (OECD 487) incidence revealed a negative outcome with metabolic activation by S9-mix, which does not show a toxification effect.

In addition to the consideration of the parental substance, metabolism studies (as summarized by Ball et al., 2012) gave indications of the possible metabolites of DiPT.

The described metabolic pathway ofterephthalate esters in the published category approach byBall and co-workers (2012)isassumed also for DiPT. Ball et al. (2012) concluded that the category members are all hydrolyzed by esterase enzymes to TPA and the respective alcohol moieties while the hydrolysis rate can differ mainly in the rate of metabolism, particularly concerning the second ester linkage. Furthermore, rapid hydrolysis in vitro of comparable diesters like di-n-butyl terephthalate and 2-ethylhexyl methyl terephthalate (Batelle, 2007) indicates limited systemic availability of DiPT as parent ester.

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product.

Possible excretion ways of the metabolites of DiPT are primary urine and secondary feces and expired air. Furthermore, it can be assumed that the parent compound DiPT israrely excreted especially via urine due to its lipophilicity (Ball et al., 2012; Lessmann et al., 2016).

 

Literature

Ball GL, McLellan CJ, Bhat VS. Toxicological review and oral risk assessment of terephthalic acid (TPA) and its esters: A category approach. Crit Rev Toxicol. 2012 Jan; 42(1):28-67.

Battelle Center for Biological Monitoring and Modeling. Terephthalate metabolism in the rat: 2-ethylhexyl methyl terephthalate (MeEHT), methyl-butyl terephthalate (MeBT) and di-butylterephthalate (DBT). Final report dated December 7, 2007 of Battelle Project No. 52126 conducted for Eastman Chemical Company.

 

ECHA. Evaluation of new scientific evidence concerning DINP and DIDP. In relation to entry 52 of Annex XVII to REACH Regulation (EC) No 1907/2006. Final review report, 2013.

Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance, European Chemicals Agency, ECHA-14-G-06-EN, November 2014.