4-isopropyl-m-cresol

Endpoint summary

Description of key information

Parathymol is bioavailable via oral route. Limited systemic absorption via inhalation and dermal route is anticipated. The substance will cross cellular barriers or may be distributed into fatty tissues. Parathymol is expected to be mainly excreted in urine as unchanged or as their glucuronide and sulfate conjugates.
The bioavailability of parathymol should be limited following exposure by inhalation and by dermal route.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

In accordance with the section 8.1.1 of Annex VIII of Regulation (EC) No 1907/2006 (REACH), the toxicokinetic profile of the registered substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information collated in the dossier. The physical chemical characteristics of Parathymol, the results obtained from acute, repeated-dose, and reproductive toxicity studies, as well as information gained from genotoxicity assays were used to predict its toxicokinetic behaviour.

Physico chemical characteristics

Parathymol has a relatively low molecular weight of 150.2 g/mol. The substance is considered as moderately water soluble solid (210 mg/L) and not volatile according to its vapour pressure (1.81 Pa at 25°C). Moreover, 99.75% of its needle-like or rod-like particles have a granular size larger than 100 µm and are therefore not expected to be inhalable. Furthermore, Parathymol has low potential for bioaccumulation since it is moderately lipophilic based on the octanol/water partition coefficient (log Kow = 3.43).

Absorption

The physical chemical characteristics described above suggest that Parathymol is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being rather lipophilic than hydrophilic, it may be expected to cross gastrointestinal epithelial barriers and the absorption may be enhance by the ability of parathymol to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface. However, an acute oral gavage toxicity studies identified no evidence of systemic toxicity, i.e. neither mortality nor clinical/macroscopic effects (LD50 > 2000 mg/kg bw). The combined repeated dose toxicity with the reproduction/developmental screening test using the oral route (diet) gave a NOAEL of 1000 mg/kg bw/day (highest dose level tested, 15000 ppm). Increased liver and kidney weight and few haematological changes (prothrombin time, activated partial thromboplastin time, eosinophil counts) were considered to be part of an adaptive response to an increase in metabolic demand at the highest dose. The lack of significant adverse findings following oral dosing may be due to a very low inherent toxicity of Parathymol. However, the observation of non-adverse systemic effects, indicates the oral bioavailability of Parathymol and/or its metabolites.

Regarding the dermal absorption, this must be limited by the physical form as solid of Parathymol. However, being lipophilic (log Kow = 3.43), the rate of uptake of Parathymol into the stratum corneum is expected to be high while its moderate water solubility is not in favour of a high rate of transfer between the stratum corneum and the epidermis. Although no study was available on Parathymol, these assumptions are supported by the absence of systemic effects following a single-dose dermal application of parathymol up to 2000 mg/kg bw which would suggest a limited systemic absorption through cutaneous barriers. Moreover, enhanced skin penetration is not expected since Parathymol is not a skin irritant or corrosive.

The potential for inhalation toxicity was evaluated in a GLP study conducted according to OECD test Guideline No. 403 without any deviation. The combined inhalational LC50 was greater than 1.41 mg/L (mean maximum attainable atmosphere concentration). Non- serious clinical signs (increased respiratory rate, hunched posture and pilo-erection) and no macroscopic effects (that may indicate absorption of Parathymol were observed in the animals. In any cases, the vapour pressure and the granulometry of Parathymol indicated an absence of volatility and inhalability and therefore no exposure by inhalation is anticipated. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance.

Distribution

Systemic distribution of Parathymol can be predicted from its physical chemical characteristics. Considering that the substance is lipophilic (log Pow 3.4) and moderately water soluble, it is suggested that, upon systemic absorption, Parathymol may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. Afterwards, based on its lipophilic character, the substance will readily cross cellular barriers or will be distributed into fatty tissues with a low potential to accumulate (see section 4.7).

Metabolism

The results of the combined repeated dose toxicity with the reproduction/developmental screening test repeated oral toxicity study in the rat showed liver changes that are consistent with the increased metabolism associated with detoxification of a xenobiotic. This liver induction confirmed that a non-negligible part of Parathymol can be absorbed in gastrointestinal tract. Moreover, results of metabolism studies conducted in rats with Thymol can be considered in a read-across approach since this substance is a structural analogue of Parathymol. Therefore, it has been demonstrated that an extensive oxidation of the methyl and isopropyl groups occurred. This resulted in the formation of derivatives of benzyl alcohol and 2-phenylpropanol and their corresponding carboxylic acids (CIR, 2006). Ring hydroxylation was only a minor reaction (see attached Figure: Proposed metabolism of Thymol in rats).

Elimination

Parathymol having a molecular weight lower than 300, it is expected to be mainly excreted in urine and no more than 5-10% may be excreted in bile. Based on read-across approach with Thymol results (CIR, 2006), it is expected that Parathymol is excreted unchanged or as their glucuronide and sulfate conjugates. The substance amount that may not be absorbed from the gastro-intestinal tract, following oral ingestion, will be excreted in the faeces.

Following dermal exposure, lipophilic substances, such as Parathymol, that have penetrated the stratum corneum but not totally penetrated the viable epidermis based on limited rate, be sloughed off with skin cells.

Cosmetic Ingredient Review (CIR) expert panel (2006)Final Report on the Safety Assessment of sodium p-chloro-m-cresol, p-chloro-m-cresol, chlorothymol, mixed cresols, m-cresol, o-cresol, p-cresol, isopropyl cresols, thymol, o-cymen-5-ol and carvacrol. International Journal of toxicology, 25(Suppl.1):29-127.