1,3,5-triisopropylbenzene

Endpoint summary

Description of key information

Based on considerations of the physicochemical properties, transient symptoms of clinical toxicity following inhalation dosing, as well as the systemic effects following short-term repeated oral dosing in rats, 1,3,5-triisopropylbenzene would be expected to be absorbed by these routes in the mammalian system. Conservative absorption rates for this substance are set at 100% for oral, 100% for inhalation, and 10% for dermal.

Clinical observations and the physicochemical properties of the substance suggest that there will be some distribution of the substance into fatty tissues and organs such as the liver, kidney and spleen. The substance is expected to be metabolised to glucuronide and/or sulphate conjugates. Ultimately the majority of excretion is expected to be urinary but might also be faecal following oral dosing. Based on the available data, in particular the log P value of 6.68, the water solubility of 0.73 mg/L, and the increase in water solubility of the glucuronide and sulphate conjugates, the substance is expected to have a low potential to bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

To date, no relevant analytical toxicokinetic testing data has been generated for 1,3,5-triisopropylbenzene. However, toxicological information following oral, dermal, and inhalation exposure of 1,3,5-triisopropylbenzene and information on the physicochemical properties can be used as a basis for the assessment of toxicokinetics.

Absorption

The diffusion of a substance across biological membranes in a test species is governed by the physicochemical properties of the substance, particularly its molecular size, log P, and water solubility (ECHA, 2017). The molecular size of 1,3,5-triisopropylbenzene is 204 g/mol, which would suggest favourable gastrointestinal absorption characteristics; however, in contrast, the substance has a high log P value of 6.68 and a low water solubility of 0.73 mg/L, which suggests it would be poorly absorbed and may behave as a lipophilic substance. While passive diffusion of lipophilic substances is unlikely, lipophilic compounds (high log P and low water solubility) may be taken up by micellular solubilisation following oral exposure.

The low measured vapour pressure (0.91 Pa at 25°C) and high measured boiling point (249.5°C) of the substance would suggest it exhibits low volatility and thus likely not readily available for inhalation as a vapour.

With respect to dermal absorption, the low water solubility (0.73 mg/L) and high log P value (6.68) of the substance suggests that its lipophilic characteristics would not favour dermal uptake and therefore absorption across the skin is expected to be low.

Oral

Due to its relatively small molecular size of 204 g/mol there is a possibility of passive absorption of 1,3,5-triisopropylbenzene following oral exposure; however, this would be limited due to its lipophilic characteristics including its measured high log P value of 6.68 and low water solubility of 0.73 mg/L. These lipophilic characteristics do suggest that uptake by micellular solubilisation could be the predominant absorption mechanism.

Based on the results of the acute oral toxicity rat study, the substance has a relatively low acute oral toxicity (LD50 > 2000 mg/kg bw) and there was no indication of adverse effects on any organs during necropsy. In a 28-day, repeated dose oral study in rats, adverse effects indicative of systemic absorption were reported, notably statistically significantly increased liver weight, increased cholesterol and aspartate aminotransferase (AST) levels compared to control animals. Based on a consideration of the substance’s physicochemical properties and the available oral toxicity studies, a conservative default value for oral absorption of the substance is set as 100%.

Inhalation

The low measured vapour pressure (0.91 Pa at 25°C) and high measured boiling point (249.5°C) of the substance would suggest it possesses low volatility and thus likely not readily available for inhalation as a vapour. However, the lipophilic nature of the substance (high log P value, low water solubility) would suggest that it would have the potential to cross the alveolar and capillary membranes. While the available acute inhalation toxicity study in rats indicated a low acute aerosol inhalation toxicity value (LC50 > 5.0 mg/L), transient clinical signs indicating discomfort were reported within 1 hr of exposure. This implies some level of absorption of the inhaled aerosol substance may have occurred. Based on a consideration of the physicochemical properties and the available oral and inhalation toxicity studies, a conservative default value for inhalation absorption of the substance is set as 100%.

Dermal

The substance exhibits a low water solubility (0.73 mg/L) which would suggest that dermal uptake would likely be low. Additionally, based on its high log P value (6.68), the rate of transfer between the stratum corneum and the epidermis may be slow and will limit absorption across the skin. It is generally assumed that substances with a high log P value may also have slow uptake into the stratum corneum (ECHA, 2017). The substance was identified as a skin sensitizer at a concentration of 25% w/w in the in vivo local lymph node assay (LLNA) in mice. This would suggest that some uptake must have occurred although it may only have been a small fraction of the applied dose. Given the high log P value of the substance, the lipophilic substance may have penetrated the lipid rich stratum corneum, but was not absorbed systemically. This assumption is supported by the low acute dermal toxicity value (LD50 > 2000 mg/kg bw) reported in the acute dermal toxicity study in rats. The substance was also reported to be non-irritating in the in vivo acute skin irritation study in rabbits, indicating that the substance does not enhance penetration by causing damage to the skin surface. Based on a consideration of the substance’s physicochemical properties and the results of the available skin toxicity, irritation, and sensitisation studies, a conservative value of 10% skin absorption is chosen.

Distribution

No significant signs of systemic toxicity were reported following acute oral or dermal exposure to the substance. Clinical signs of discomfort were reported shortly after dosing via the inhalation pathway, however these were transient in nature. Sub-chronic repeated oral exposure to the substance did result in adverse effects to liver morphology and blood serum biochemistry, which suggests the substance does distribute in the animal system at least to some degree.

The substance’s high lipophilicity (high log P value) suggests that it is likely to cross cell membranes and distribute into cells. The intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. The high log P value combined with the low water solubility would allow for distribution of any absorbed substance to such organs as the liver, kidney and spleen.

Metabolism

As a lipophilic substance, 1,3,5-triisopropylbenzene is anticipated to undergo Phase I and Phase II enzymatic metabolism and ultimately be metabolized to glucuronide and/or sulphate conjugates following oral dosing. Substances with high log P values (≥ 4) tend to have longer biological half-lives due to increase fat solubility, therefore, daily repeated exposure to 1,3,5-triisopropylbenzene could have the potential overcome metabolism and clearance mechanisms and accumulate the body; however, this would only be expected to occur under very high and repeated dosing scenarios as generally, the liver of humans has a high capacity for Phase I and Phase II biotransformation reactions.

Excretion

Following metabolism to the glucuronide and/or sulphate conjugates, ultimate excretion is expected to be primarily urinary, although a minor amount of faecal excretion may also occur following oral dosing. 

Based on the available data, in particular the log P value of 6.68, the low water solubility of 0.73 mg/L and the increase in water solubility of the glucuronide and sulphate conjugates, the substance is expected to have a low potential to bioaccumulate in animals and humans.

 

REFERENCES

 

ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Volume 3.0, July 2017. Available at: https://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450-cc0dfa7988e5