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Description of key information

The substance 6'-(dibutylamino)-3'-methyl-2'-(phenylamino)spiro[isobenzofuran-1(3H),9-(9H)-xanthen]-3-one (ODB-2) is a white powder. It is an organic monoconstituent (>98 -100% (ca. 99.7%)) . 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, 28 day repeated dose, subchronic reproductive 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.

 

The available physicochemical and toxicological data suggests that oral absorption is expected to be low and mainly via the lymphatic system.  The available physicochemical and toxicological data suggests that absorption of ODB-2 via the dermal routes is expected to be minimal. The available physicochemical data suggests that absorption of ODB-2 via the inhalation route is expected to be low but no inhalation studies are available for the substance. Initial systemic exposure is likely to be to the parent compound as first-pass metabolic transformation is avoided. Wide distribution of ODB-2 is not expected. The substance is expected to be excreted as the mainly unchanged parent form the faeces.

 

The absorption rates of 50% (oral), 10% (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 (%):
10
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 ODB-2 in the body. This information can be combined with the in vivo study data for the toxicokinetic assessment.

 

Absorption – oral

The molecular weight of ODB-2 (532.68 g/mol) is slightly above the range for favourable oral absorption (<500 g/mol). The log P of ODB-2 (4.66) indicates it is highly lipophilic and a water solubility of 0.021 mg/L indicates ODB-2 is highly insoluble in water. These characteristics will not facilitate transport of ODB-2 via passive diffusion and impair its ability to dissolve in gastric juices. Oral absorption from the GI tract via the portal vein system is unlikely. Based on its high lipophilicity, the absorption of ODB-2 via the lymphatic system through micellular solubilisation by bile salts is a possibility.

 

The acute oral study (LD50: >5000 mg/kg) and subchronic oral reproductive study (NOAEL: 1000 mg/kg bw/day) data did not indicate any treatment-related effects. The oral 28 day repeated dose study data (NOAEL: 1000 mg/kg bw/day) indicated that some oral absorption may have occurred. The in vivo study data together with the physicochemical information indicates that the substance is poorly absorbed via the oral route; any absorption and systemic effects noted may be due to uptake via the lymphatic system. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

 

Absorption - dermal

The physical state, molecular weight (532.68 g/mol), Log P (4.66) and insolubility in water (0.021 mg/L) indicate that dermal absorption is unlikely. The acute dermal toxicity study did not indicate any effects up to the limit dose (LD50: >2000 mg/kg). The in vivo skin irritation study in rabbits and skin sensitisation study in guinea pigs indicated that the substance is not irritating or sensitising. The log P is an indication for a high uptake into the stratum corneum, but a limited rate of penetration into the lower layers of the epidermis and dermis; as no systemic effects were noted in any dermal toxicity study, it can be assumed that there is negligible systemic 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. As ODB-2 meets the former criteria, and the in vivo study data also indicate minimal dermal absorption, a dermal absorption rate of 10% is accepted for chemical safety assessment purposes.

 

Absorption - inhalation

The particle size distribution report for ODB-2 indicates a range of 0.138 µm to 138.038 µm (d(0.1)=2.761 um, d(0.5)=13.691 um and d(0.9)=44.819 um). This range indicates the availability of ODB-2 in the inhalable and respirable fractions of air. Based on the molecular weight (532.68 g/mol), Log P (4.66), insolubility in water (0.021 mg/L) and vapour pressure (2.71 e-7 Pa), ODB-2 particles may either be transported out of the respiratory tract through clearance mechanisms and swallowed, or to a lesser extent, absorbed directly from the respiratory tract. In both cases, the absorption of ODB-2 via the lymphatic system through micellular solubilisation is possible and absorption is expected to be low. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, as no inhalational toxicity data is available for the substance.

 

Distribution/Metabolism

The molecular weight (532.68 g/mol) and water solubility of 0.021 mg/L of ODB-2 are unfavourable for wide distribution. The log P (4.66) is an indication for a high uptake into the stratum corneum, but a limited rate of penetration into the lower layers of the epidermis and dermis; any ODB-2 that persists after dermal exposure may be sloughed off with skin cells. The subchronic oral reproductive toxicity study or 28-day repeated dose studies did not indicate any specific target organ or tissue toxicity and ODB-2 is not likely to distribute widely and is unlikely to accumulate. There is no direct evidence to indicate how the substance is metabolised. As oral absorption via the portal vein is unlikely, any ODB-2 that may be absorbed via the lymphatic system will not be subject to first pass metabolism and initial systemic exposure will be to the parent compound.

There is no direct evidence to indicate the route of excretion of the substance. Based upon the molecular weight (532.68 g/mol) and water solubility of 0.021 mg/L, it is likely that excretion of unchanged ODB-2 will be in the faeces via bile/directly from the gastrointestinal mucosa.