Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance Ligustral/Cyclal C/Trigustral is a multi-constituent organic liquid. It has 2 main constituents: 3-Cyclohexene-1-carboxaldehyde, 2,4-dimethyl-, (1R,2S)-rel- (CAS No. 188716-52-1) which has a typical concentration of 57% and 3-Cyclohexene-1-carboxaldehyde, 2,4-dimethyl-, (1R,2R)-rel- (CAS No. 444880-20-0) which has a typical concentration of 23%. There is one impurity 3,5-dimethylcyclohex-3-ene-1-carbaldehyde which is in a range of 0 - 32%.
A full ADME toxicokinetic study in the rat is not available. The toxicokinetic analysis is based on data from in vivo animal models and physicochemical data. In vivo studies for the acute oral and dermal routes are available for Ligustral/Cyclal C/Trigustral. In vivo skin and eye irritation and skin sensitisation studies are available for Ligustral/Cyclal C/Trigustral. In vivo read across studies from 3 and 4-(4-Hydroxy-4-methylpentyl)-3 -cyclohexene-1-carboxaldehyde (HMPCC) for the subacute and subchronic oral routes are available. There are no studies covering the inhalational route available. Further details on endpoints are available in the IUCLID 5 registration dossier.
Based on the physicochemical properties and information in the dossier (Ligustral/Cyclal C/Trigustral studies and HMPCC read across studies), Ligustral/Cyclal C/Trigustral is expected to be absorbed after oral, inhalation and dermal exposure. Ligustral/Cyclal C/Trigustral is likely to be widely distributed and converted to water soluble metabolites to facilitate excretion. Based on the substance data, the absorption rates of 50 % (oral), 50 % (dermal) and 100 % (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour ofLigustral/Cyclal C/Trigustralin the body.

Absorption

The molecular weight (138.2 g/mol), octanol/water partition coefficient (log Kow: 2.7 at 25°C) and water solubility (0.91g/Lat 20°C) of Ligustral/Cyclal C/Trigustral favour absorption via passive diffusion. Based on the chemical structure, Ligustral/Cyclal C/Trigustral has no groups which will dissociate in a relevant pH range (2-10) so is likely to be present in the body in a non-ionised form. These characteristics will facilitate transport of Ligustral/Cyclal C/Trigustral across lipid cell membranes and therefore oral absorption. Ligustral/Cyclal C/Trigustral is moderately soluble in water (0.91 g/L at 20°C) and has a moderate log Kow value which indicates favourable absorption directly across the respiratory tract epithelium by passive diffusion. However, due to the low vapour pressure of Ligustral/Cyclal C/Trigustral (36 Pa at 20°C) and physical form exposure via the inhalation route is expected to be low. The physical state of Ligustral/Cyclal C/Trigustral, low vapour pressure (36 Pa at 20°C), molecular weight (138.2 g/mol), moderate water solubility (0.91 g/L at 20°C) and optimal log Kow (2.7 at 25°C) are indicative of favourable dermal absorption.

Distribution/Metabolism

A wide distribution ofLigustral/Cyclal C/Trigustralis favourable as it has a relatively small molecular weight, moderate lipophilicity and is present in a non-ionised form in the body. Based on the log Kow value (2.7 at 25°C),Ligustral/Cyclal C/Trigustralis unlikely to accumulate with intermittent exposure but may be possible with repeated exposure. The physicochemical properties ofLigustral/Cyclal C/Trigustral(low molecular weight, lipophilic, non-ionised) suggests it can cross the placenta.

Based on the chemical structure and using theSMARTCyp - Cytochrome P450 - Mediated Metabolism simulator (Toxtreev2.5.0),the primary and secondary sites of metabolism of the both the target and source chemicals are estimated to be oxidation of the aldehyde to a carboxylic acid group and aliphatic hydroxylation respectively.Both of these reactions may be followed by Phase II conjugation with glucuronic acid to yield polar metabolites.

Excretion

The substance is expected to be excreted in theurine due to its low molecular weight (<300) and good water solubility.Postnatal exposure via the milk during lactationmay also be a minor route of excretion.

Information from other studies in the dossier

Oral/GI absorption

Systemic effects were noted in theLigustral/Cyclal C/Trigustralacute oral toxicity study andHMPCCread across28-dayrepeated dose oral toxicity studies; it is assumed that oral absorption of Ligustral/Cyclal C/Trigustral occurs during repeated exposure.Thein vivostudy data together with the physicochemical informationare indicative of favourable oral absorption. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, a default oral absorption of 50% is accepted.

Dermal absorption

The data from the acute dermal studyin rabbits indicated that dermal absorption occurs as systemic effects were observed.The skin sensitisation study in guinea pigs indicated that Ligustral/Cyclal C/Trigustralis classified for skin sensitisation, which also suggests that systemic exposure occurs. The in vivo study data together with the physicochemical informationare indicative of favourable dermal absorption.The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Respiratory absorption-Inhalation

There are no inhalation studies available for the substance. For chemical safety assessment, based on the physicochemical properties, an inhalation absorption rate of 100% is accepted.

Distribution/Metabolism

From the HMPCC read across studies (28 day repeated dose oral toxicity study and one generation developmental study), there is evidence of a wide distribution withhistopathological changes in theliver and kidney noted at high dosages (1000 mg/kg bw/day) in the 28 day repeated dose oral toxicity study);it is assumed that similar distribution may occur for Ligustral/Cyclal C/Trigustral.There is no direct evidence to indicate how the substance is metabolised. Thein vivostudy data together with the physicochemical informationare indicative of favourabledistribution and metabolism during Phase I and Phase II reactions to polar metabolites.

Excretion

There is no direct evidence to indicate the major route of excretion of the substance.Ligustral/Cyclal C/Trigustralis expected to be excreted in the urine due to itslow molecular weight (<300) and good water solubility, which will be increased during metabolic transformation.Postnatal exposure via the milk during lactationwas a minor route of excretion for HMPCC; there is a possibility thatLigustral/Cyclal C/Trigustral may also be excreted via this route.