Cyclohexane, 1-methyl-4-(1-methylethyl)-, tetradehydro deriv.

Endpoint summary

Description of key information

Depanol I is considered to be absorbed by oral, inhalation and dermal route, however the oral route is most appropriate for testing. Deposition of Depanol I in the inhalation tract is not expected from its rather low vapour pressure, whereas repeated dermal administration is to be avoided due to its sensitizing properties. From one of  the major components, d-limonene, it is known to be rapidly absorbed, metabolised and excreted, therefore there is no bioaccumulation potential. The  various terpene hydrocarbons, which are known to be food flavor ingredients, have been described to be very similar from a kinetics and safety viewpoint. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

80

Absorption rate - dermal (%):

80

Absorption rate - inhalation (%):

80

Additional information

Depanol I is a colourless, neutral solvent with a terpene-like odour, low molecular weight (140.265), low water solubility (3.6- 5.9 mg/L) and has a Log Pow in the range of 4.75-4.88. Although the acute oral toxicity study did not show any findings, oral absorption is assumed to be relevant and the most appropriate route for testing. Based on the low vapour pressure (1.3 mm Hg or 230 Pa at 20°C ), deposition in the airways is considered to be very low to non-relevant, although the acute inhalation toxicity study showed some clinical observations. Finally, dermal absorption is possible as also calculated by Dermwin simulation, however as it is a sensitizer, it is not the preferable route of testing. For risk characterization, an absorption rate of 80% was considered for all routes from a conservative viewpoint.

Based on the low molecular weight and the high LogP of Depanol I, distribution is considered to be possible. This is confirmed by the presence of some CNS signs of toxicity during inhalation, although these findings may also have been due to discomfort. In general no relevant target organs for humans have been described in repeated-dose toxicity testing with (d-)limonene and other terpene hydrocarbons (components of Depanol I). There is no direct indication of bioaccumulation potential in mammalian species. There may be some accumulation in adipose tissue, but only in case of daily exposure. However this is not indicated from the repeated dose toxicity testing with d-limonene and other terpene hydrocarbons. Based on the rapid absorption, metabolic detoxification, and excretion in humans and other animals, bioaccumulation is not expected. Excretion has been well studied for d-limonene, where the metabolic pathway shows various water soluble metabolites. Several possible pathways of metabolism were described for d-Limonene, with differences between species. About 25–30% of an oral dose of d-limonene in humans was found in urine as d-limonene-8,9-diol and its glucuronide; about 7–11% was eliminated as perillic acid (4-(1- methylethenyl)-1-cyclohexene-1-carboxylic acid) and its metabolites. In another study, perillic acid was reported to be the principal metabolite in plasma in both rats and humans. Other reported pathways of limonene metabolism involve ring hydroxylation and oxidation of the methyl group. See more information in separate Toxicokinetics document attached to Section 13.

As Depanol I is composed of various terpene hydrocarbons, read across with the components or similar substances was applied. The monoterpene hydrocarbons are known to be ‘generally recognized as safe’ as flavor ingredients, which has recently been reaffirmed (GRASr). This was based on the knowledge of their rapid absorption and metabolic conversion, their wide safety margins and lack of genotoxic and mutagenic potential. The consistency of the results support the conclusion that terpene hydrocarbons in the food supply is not associated with significant risk to human health. Based on the safe profile, the similar properties between substances and the availability of extensive data, read across with some ‘typical’ examples was considered to be appropriate to fill the data gaps.

Data rich source compounds have been discussed in a separated 'read across justification', including both aliphatic (mono- and bicyclic) and aromatic terpene hydrocarbons. D-limonene can be used as source chemical based on the similar structure, physicochemical and toxicological findings. Various anchorpoints were available; confirming validity as read across for the repeated and reproductive toxicity, however for developmental toxicity data were still missing. Therefore a second (aromatic) source chemical was selected, i.e. alfa-methylstyrene, which also demonstrated a similar structure and similar physicochemical and toxicological properties. Therefore, a many-to-one read across approach was used for Depanol I. See more information in separate Toxicokinetics document attached to Section 13.