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Description of key information

Considering the physico-chemical properties and the available toxicologcial data it is assumed that inhalation, oral and dermal absorption is very restricted and follows a ratio of 8:4:1, respectively. There is no bioaccumulation potential (BCF of 364.3 L/kg ww).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicological profile of the substance

 

With regard to acute toxicity, neither death nor signs of systemic toxicity occurred in an acute oral and dermal toxicity test at the limit dose of 2000 mg/kg bw. The substance did not cause signs of skin irritation in the rat acute dermal toxicity study as well as in the rabbit dermal irritation patch test (OECD 404) and induced only slight and transient signs of irritation in the rabbit eye irritation study (OECD 405) without relevance for classification and labeling. No skin sensitising effect was observed in the guinea pig maximisation test.

 

In a 28-d oral toxicity study with rats (OECD 407), no findings of toxicological relevance were observed at the highest dose level of 1000 mg/kg bw/d for male and female animals. Therefore the NOAEL in this study was 1000 mg/kg bw/d for male and female animals.

In an oral reproduction/developmental toxicity screening test in the rat (OECD 421) Fadex HE 1819 PK did not cause any adverse effect attributable to substance administration in parental or offspring animals. The NOAEL was 1000 mg/kg bw/d for systemic, reproductive and developmental toxicity.

 

In an in vitro bacterial assay (OECD 471) and gene mutation assay in V79 cells (OECD 476) no gene mutagenic activity of the substance was demonstrated. The substance did not induce chromosome aberrations in an in vitro assay with CHL cells (EU method B.10).

 

Toxicokinetic assessment

 

No test data was available on the toxicokinetic behavior of the substance. The substance is a yellow solid with a molecular weight of appr. 484.5 g/mol. The water solubility is reported as < 0.0352 mg/L at 20 °C. The partition coefficient between octanol and water (log Kow) is > 4.19 (at 21.5 °C) and a BCF of 364.3 L/kg ww was calcuated. It has a very low vapour pressure (< 0.00028 Pa at 25 °C).

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. In contrast, the very low water solubility of < 0.0352 mg/L does not enable the substance to readily dissolve in the gastrointestinal fluids and the molecular weight clearly above 200 prevents that the substance can pass through aqueous pores or be carried via carriage of the molecules across membranes with the bulk passage of water. The log Pow value of > 4.19 is not favorable for passive diffusion, but might enable the substance to be taken up by micellular solubilisation. The latter mechanism is of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed (ECHA, 2014). Taken together, the physiochemical properties indicate that oral absorption of Fadex HE 1819 PK is rather limited.

Inhalation of substance vapours is considered as negligible due to the low vapour pressure of < 0.00028 Pa at 25 °C. Exposure to particles which could reach the alveolar region of the respiratory tract is also limited as only a small fraction of the substance (1%) has a particle size below 10 µM. If in the alveolar region of the lungs similar considerations for absorption apply as for the oral absorption, leading to the conclusion that inhalation absorption is restricted. For DNEL derivation it is assumed that inhalation absorption is twice as high as oral absorption.

As the substance is a dry particulate of a molecular weight close to 500 and has a water solubility < 0.0352 mg/L at 20 °C, dermal absorption is expected to be very low. For DNEL derivation it is assumed that dermal absorption is four fold lower than oral absorption.

 

Distribution

The available toxicity data do not allow a conclusion on distribution due to the lack of any substance related response. Based on the low water solubility and high log Pow distribution into cells of the fatty tissues might be expected if absorption occurs. Following dermal contact penetration into the lipid rich stratum corneum and persistence therein might be expected. Eventually the substance is cleared as the stratum corneum is sloughed off. A bioaccumalation is not expected due to the low BCF of 2.56.

 

Metabolism

Based on the structure of the molecule it may be metabolized by Phase I enzymes while undergoing functionalization reactions aiming to increase the compound’s hydrophilicity. The substance is most likely not enzymatically activated (toxified) during metabolism. This assumption is supported by the available toxicity data which did not reveal a toxic effect. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the parent compound or the Phase I metabolite in order to ultimately facilitate excretion.

 

Excretion

The substance demonstrates a quite insignificant adsorption and is presumably rapidly excreted (preferentially in the faeces). Excretion of putative metabolites is expected to occur via the urine and the faeces depending on the physicochemical characteristics of the degradation products.

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