1,3-diisopropylbenzene

Basic toxicokinetics

Administrative data

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: expert statement based on the ECHA Guidance R.7c

Data source

Reference

Reference Type:

review article or handbook

Title:

Guidance on Information Requirements and Chemical Safety Assessment; Chapter R.7c: Endpoint specific guidance, version 3,

Author:

ECHA

Year:

2017

Bibliographic source:

ISBN 978-92-9495-838-9

Materials and methods

Objective of study:

absorption

distribution

enzyme clearance

excretion

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

expert assessment of ADME based on the ECHA Guidance R.7c

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,3-diisopropylbenzene

EC Number:

202-773-1

EC Name:

1,3-diisopropylbenzene

Cas Number:

99-62-7

Molecular formula:

C12H18

IUPAC Name:

1,3-bis(propan-2-yl)benzene

Test animals

Sex:

male/female

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral absorption
Generally the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption; molecular weights above 1000 do not favour absorption. Moderate log P values (between -1 and 4) are favourable for absorption by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P > 4), particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed. 1,3-Diisopropylbenzene has a molecular weight of 162 g/mol, a low water solubility (72 µg/L) and a high logP (5.13). Thus, absorption by micellular solubilisation is favoured for the substance. Systemic availability after oral absorption is also indicated by the available Repeated dose toxicity study, where slight effects on the liver and kidney were found.
Taken together, based on the available studies in combination with the physical-chemical properties an oral absorption rate of 100 % is assumed for 1,3-diisopropylbenzene as worst-case.


Dermal absorption
Absorption in the stratum corneum is favoured for substances with a molecular weight below 100 g/mol, but it is also possible for substances with a molecular weight of below 500 g/mol. To cross the lipid-rich stratum corneum a certain degree of lipophilicity is required. Log P values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore, if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Uptake into the stratum corneum itself may be slow. 1,3-Diisopropylbenzene has a molecular weight of 162 g/mol, a low water solubility (72 µg/L) and a high logP (5.13). Thus, 1,3-diisopropylbenzene is expected to be able to be absorbed by the stratum corneum. To partition from the stratum corneum into the viable part of the epidermis, a substance must be sufficiently soluble in water (> 1 mg/L). Having a water-solubility of 0.072 mg/L 1,3-diisopropylbenzene is hardly able to partition from the stratum corneum into the lower epidermis and thus, be taken up by the systemic circulation. Therefore, dermal absorption is very limited. Thus, a default value of 10 % (for substances with a logP > 4) is used for dermal absorption according to ECHA Guidance R. 7c.


Respiratory absorption
The substance is liquid. Therefore, it is not available for inhalation as particle. Due to the vapour pressure of 57 Pa at 25 °C and a boiling point of 203 °C, 1,3-diisopropylbenzene has a low volatility and thus it is unlikely to be available as a vapour. If, however absorbed, 1,3-diisopropylbenzene is favourable for absorption by micellular solubilisation based on its high logP value of 5.13 and low water solubility of 0.072 mg/L.
Based on the available data, it can be concluded that inhalatory exposure is unlikely. However, respiratory absorption cannot be fully excluded. Thus, as worst-case, 100 % inhalation absorption is assumed.

Details on distribution in tissues:

Due to the low molecular weight (162 g/mol) 1,3-diisopropylbenzene is expected to be widely distributed in the body. As the molecule is lipophilic (log P > 0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. As the substance has a logP above 4, accumulation in fatty tissue cannot be excluded. Also, based on its high lipophilicity it can readily penetrate the lipid rich stratum corneum when in contact with the skin. As it is too liphophilic to be absorbed systemically, it may persist in the stratum corneum and eventually be cleared as the stratum corneum is sloughed off.

Details on excretion:

1,3-Diisopropylbenzene is expected to be metabolized by Cytochromes P450 enzymes. Main targets are the isopropyl-chains. In phase I metabolism hydroxyl-groups are expected to be attached to the isopropyl-chains. In phase II metabolism glucuronide or glutathione conjugation may occur at the isopropyl-chains. These pathways were shown in a study with the structural analogue isopropylbenzene in rats and mice (Chen et al. 2011). By the attachment of these polar groups, the polarity of the substance is increased. The low molecular weight and the polarity of these metabolites favour urinary excretion. Therefore, the main excretion route is expected to be urinary excretion. A minor percentage of the metabolites will also be excreted via the bile. This was also shown for the analogue isopropylbenzene (Chen et al. 2011).

Applicant's summary and conclusion

Conclusions:

The absorption rate of 1,3-diisopropylbenzene is assumed to be 100 % via the oral and inhalation and 10 % via dermal route. The substance is expected to be distributed widely through body, while the intracellular concentration is expected to be higher than the extracellular concentration. Accumulation in the fatty tissue and the stratum corneum may occur. The main excretion route is urinary excretion.

Executive summary:

The ADME parameters were assessed based on stability data, available toxicological studies and physico-chemical properties in accordance with ECHA Guidance R.7c.

The absorption rate of 1,3-diisopropylbenzene is assumed to be 100 % via the oral and inhalation and 10 % via dermal route. The substance is expected to be distributed widely through body, while the intracellular concentration is expected to be higher than the extracellular concentration. Accumulation in the fatty tissue and the stratum corneum may occur. The main excretion route is urinary excretion.