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 Flyadd-3 is a white solid. It is a mono constituent organic substance (>= 99.64%) with <= 0.36% impurities.
No studies on the toxicokinetics of the substance are available. Only limited data has been provided by ECHA via an inquiry result. No human data is available and the toxicokinetic analysis is based on data from physicochemical data and in vivo animal models. In vivo studies covering the oral route are available (acute and 28 day repeated dose toxicity). In vivo studies covering the dermal route are available (acute, skin irritation, skin sensitisation). There are no studies covering the inhalational route available. For further details on study summaries, reference is made to the appropriate sections in the IUCLID 5 registration dossier.
Absorption is expected to be low, wide distribution is unlikely and the substance is likely to be excreted in the faeces. 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:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

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 of Flyadd-3 in the body. This information can be combined with the in vivo study data for the toxicokinetic assessment.

Absorption:

Oral/GI absorption

The molecular weight of Flyadd-3 (414 g/mol) is in the range for favourable oral absorption (<500 g/mol). The log P of Flyadd-3 (3.4 @ 22 °C) indicates it is lipophilic and is in the range of favourable oral absorption by passive diffusion. However the water solubility (0.0476 mg/L @20°C) indicates it is poorly soluble and typically solids have to dissolve before they can be absorbed, so oral absorption is expected to be low. The acute oral toxicity study did not indicate any effects up to the limit dose (LD50: >5000 mg/kg). The only change observed in the oral 28 day repeated dose studies was an increase in absolute and relative liver weights in males at 1000 mg/kg bw/day, but there was no supporting histopathological data. The NOEL was 200 mg/kg bw/day and the NOAEL was 1000 mg/kg bw/day. The in vivo study data together with the physicochemical information indicates that the substance is poorly absorbed via the oral route. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption of 50% is accepted.

Respiratory absorption-Inhalation

The particle size distribution report for Flyadd-3 indicates the following volume median diameters: d10: 0.62 µm, d50: 1.339 µm, d90: 23.491 µm. This indicates that Flyadd-3 particles have the potential to be available in the inhalable fractions of air and may reach the thoracic (<50 µm) and alveolar regions (<15 µm). As Flyadd-3 is poorly water soluble (0.0476 mg/L), the rate at which the particles dissolve into the mucus will limit the amount that can be absorbed directly. The fraction that may reach the thoracic region will mainly be cleared from the lungs by the mucocilliary mechanism and swallowed (see oral absorption). The fraction that may reach the alveolar region would mainly be engulfed by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Due to the low vapour pressure (0.000001 Pa) negligible exposure via the inhalational route may be expected. However, as there is no inhalational study data available for this substance, for chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted.

Dermal absorption

The molecular weight of 414 g/mol is above the range for favorable dermal absorption (<100 g/mol). The log P (3.4) is the favourable range for dermal absorption (log P 1-4) however the physical state, and poor water solubility (0.0476 mg/L) indicate that dermal absorption is unlikely. The acute dermal toxicity study did not indicate any effects (systemic or local) up to the limit dose (LD50: >2000 mg/kg). The in vivo skin irritation study in rabbits indicted that the substance caused a mild transient erythema and in the skin sensitisation study in guinea pigs the substance was not sensitising. The available dermal toxicity data together with the physicochemical data indicates that any significant dermal absorption is unlikely. 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.

Distribution/Metabolism

The molecular weight (414 g/mol) and water solubility (0.0476 mg/L) are unfavourable for wide distribution. There is no direct evidence to indicate how the substance is metabolised. As absorption is likely to be low, Flyadd-3 is expected to be excreted unchanged in the faeces.