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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics in vivo
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

Constituent 1
Chemical structure
Reference substance name:
1,4-diisopropylbenzene
EC Number:
202-826-9
EC Name:
1,4-diisopropylbenzene
Cas Number:
100-18-5
Molecular formula:
C12H18
IUPAC Name:
1,4-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 g/mol are favourable for absorption; molecular weights above 1000 g/mol 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. 1,4-Diisopropylbenzene has a molecular weight of 162 g/mol, a low water solubility (41.5 µg/L) and a high log P (5.2). Thus, absorption by micellular solubilisation is favoured for the substance.
Taken together, based on the available studies in combination with the physical-chemical properties an oral absorption rate of 100 % is assumed for 1,4-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. 1,4-Diisopropylbenzene has a molecular weight of 162 g/mol, a low water solubility (41 µg/L) and a high log P (5.2). Thus, 1,4-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 0.41 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 41.5 Pa at 25 °C and a boiling point of 210 °C, 1,4-diisopropylbenzene has a low volatility and thus it is unlikely to be available as a vapour. If, however absorbed, 1,4-diisopropylbenzene is favourable for absorption by micellular solubilisation based on its high log P value of 5.2 and low water solubility of 41 µg/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) 1,4-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:
1,4-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. 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 1,4-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 1,4-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