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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
theoretical assessment
Type of information:
other: theoretical assessment based on physchem properties and all data available
Adequacy of study:
key study
Study period:
February 2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Remarks:
Theoretical assessment taking all currently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance. Since this is a theoretical assessment, the Klimisch value cannot be 1.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Results and discussion

Main ADME results
Type:
absorption
Results:
Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 100% (oral), 100% (inhalation) and 50% (dermal) for risk assessment purposes.

Any other information on results incl. tables

A toxicant can enter the body via the gastrointestinal tract, the lungs and the skin. In general, a substance needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration.1 KY-AF is a powder with a low water solubility (<9 μg/L) which will limit the oral absorption, while the molecular weight below 500 and the log Pow of 3.8 favour absorption. Based on these data, an oral absorption of 100% is used for risk assessment purposes. The results of the oral toxicity studies do not provide reason to deviate from this proposed oral absorption factor.

For inhaled substances the processes of deposition of the substance on the surface of the respiratory tract and the actual absorption have to be differentiated. The vapour pressure of KY-AF (7.5E-05 Pa at 20°C) is too low to enable KY-AF reaching the respiratory tract in significant amounts. KY-AF contains particles below 100 μm, which have the potential to be inspired; particles below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. For a poorly water-soluble powder as KY-AF the rate at which the particles dissolve into the mucus will limit the amount that can be absorbed directly. The log Pow of 3.8 favours absorption directly across the respiratory tract epithelium by passive diffusion. Based on these considerations, the respiratory absorption is set at 100% for risk

assessment purposes.

KY-AF has to be dissolved to penetrate the skin. The low water solubility of KY-AF indicates dermal absorption to be low. According to the criteria given in the REACH Guidance, a default value of 100% dermal absorption should be used unless MW >500 and log Pow <-1 or >4, in which case a value of 10% skin absorption should be chosen.2 KY-AF does not fulfill these criteria, but both the molecular weight and the log Pow of KY-AF are near the boundaries for these parameters. Based on these considerations, for risk assessment purposes the dermal absorption of KY-AF is set at 50%.

Once absorbed, distribution of the test substance throughout the body is expected to be low based on its low water solubility (< 9μg/L), relatively high molecular weight (464), although the partition coefficient (3.8) favours distribution. KY-AF may be expected to accumulate limitedly in adipose tissue.

REFERENCES

1 Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

2 Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, Version 6.0 November 2016.

Applicant's summary and conclusion

Conclusions:
A toxicokinetic assessment was performed based on the available data of the substance. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 100% (oral), 100% (inhalation) and 50% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.