(R)-5-isopropyl-2-methylcyclohexa-1,3-diene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Expert Statement

Type of information:

other: Expert Statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Statement, no study available

Data source

Reference

Reference Type:

other: Expert Statement

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

(R)-5-isopropyl-2-methylcyclohexa-1,3-diene

EC Number:

224-167-6

EC Name:

(R)-5-isopropyl-2-methylcyclohexa-1,3-diene

Cas Number:

4221-98-1

Molecular formula:

C10H16

IUPAC Name:

(5R)-2-methyl-5-(propan-2-yl)cyclohexa-1,3-diene

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol. The water solubility of the substance is too low to allow the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water. But, as alpha phellandrene has a water solubility of 4.37 mg/L together with a log Pow value >4, it may be taken up by micellular solubilisation. As mortality was observed in the acute oral toxicity study at higher doses, the substance was proven to be taken up by oral route. Besides that, the effects observed in the OECD 422 study (test substance-related changes in the liver in males of the 75 mg/kg bw/d dose group and in males and females of the 200 mg/kg bw/ d dose group, increased liver weights in both sexes at 75 and 200 mg/kg bw/d) also serve as a proof of uptake via the oral route.

No experimental data for exposure following the respiratory route are available. Due to the vapour pressure of 2.35 hPa (at 20 °C) of the substance, it may become available as a vapour. Absorption via inhalation route is considered possible as absorption via oral route does also take place.

Dermal uptake is favoured for substances with a molecular weight <100 g/mol, but possible for substances with a molecular weight <500 g/mol. The log Pow of alpha phellandrene is >5 and therefore 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. Dermal absorption cannot be excluded, but is not assumed to take place at high rates. The acute dermal toxicity study did not reveal any systemic effects. Signs of slight (reversible) irritation were noted in the animals, indicating skin damage that may enable penetration at low rates. In addition the substance was shown to be sensitising to skin, thus proving dermal uptake must have occurred, at least to a low extend.

Details on distribution in tissues:

As mentioned above, the physicochemical properties of alpha phellandrene allow systemic absorption following oral and dermal uptake.
In general, the smaller the molecule the wider the distribution. The results of the OECD 422 study show that the substance must reach the liver, as there were reversible histopathologically findings in males of the 75 mg/kg bw/d dose group and in males and females of the 200 mg/kg bw/ d dose group (centrilobular hepatocellular hypertrophy) as well as increased liver weights in both sexes at 75 and 200 mg/kg bw/d. Taken into account its log Pow and the water solubility, accumulation of alpha phellandrene cannot be excluded. The calculated BCF value of 2846 L/kg does further imply a bioconcentration potential of the substance. The available study data revealed no indications of the substance to cross the blood-brain barrier.

Details on excretion:

The metabolites of alpha phellandrene are most likely excreted via urine due to their small molecular weight and their enhanced water solubility.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

Metabolism mainly occurs in liver especially following oral intake.
From the in vitro genotoxicity studies no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic S9-mix could be detected, therefore not indicating metabolism to more toxic compounds in in vitro and probably also in vivo.
Due to its chemical structure the substance might probably be converted to more polar products via phase I oxidation reactions at the methyl side chain or at the isopropyl side chain. Further conjugation reactions (phase II) may also occur.
Besides that reactions taking place at the ring structure are possible as predicted by the OECD QSAR-Toolbox metabolism simulators (in vivo rat metabolism simulator, rat liver S9 mix simulator and skin metabolism simulator). The double-bonds of the ring structure are attacked resulting in epoxidation and further hydrolysation of the epoxide. Ring opening reactions are also possible.
Due to the enhanced hydrophilicity of the metabolisation products elimination via urine can take place.

Applicant's summary and conclusion

Conclusions:

Bioaccumulation of alpha phellandrene products cannot be excluded based on the available data.

Executive summary:

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the oral and dermal route may take place to a small extend. This assumption is supported by the results of the oral and dermal acute toxicity studies, revealing some effects only at very high doses, as well as the combined repeated dose oral toxicity study with the reproduction/developmental screening test. Absorption via inhalation may also take place. Bioaccumulation of alpha phellandrene products cannot be excluded based on the available data. After metabolisation, the substance will be mainly excreted via urine.