Registration Dossier

Diss Factsheets

Administrative data

basic toxicokinetics, other
Type of information:
other: Theoretical assessment
Adequacy of study:
key study
Study period:
15 February 2021
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP assessment report based on expert judgement

Data source

Reference Type:
study report
Report date:

Materials and methods

Objective of study:
Test guideline
no guideline required
Principles of method if other than guideline:
An expert assessment was made based on all data available.
GLP compliance:

Test material

Test animals

other: None

Administration / exposure

Route of administration:
other: Oral, dermal and inhalation
other: Not applicable
Details on study design:
A toxicokinetic assessment has been performed based on available physico-chemical properties and toxicological data of the substance.

Results and discussion

Any other information on results incl. tables

After exposure, a substance can enter the body via the gastrointestinal tract, the lungs and the skin. Since different parameters are relevant to estimate adsorption depending on the route of exposure, the three routes will be addressed individually.

In general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration1. The substance is an UVCB with three main constituents, which can be present in a mono- or a di-ester form. These forms show different water solubility, with the mono-form being more water soluble. This mono-form has a moderate to high water solubility (0.749 g/L (low loading rate) - 3.40 g/L (high loading rate) at 20°C). This implies that the substance dissolves to some extent in the gastrointestinal fluids and can be taken up systemically. The molecular sizes of the main constituents differ, but the molecular weight of all constituents is high (almost 500, or exceeding 500). Therefore uptake is expected to be hampered for all components, none of the constituents is able to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. It was technically not feasible to determine the partition coefficient of the substance, but based on the composition of the substance it can be expected that some components will have a high log Pow, while others will have a low log Pow. However, based on absence of further information it is difficult to predict the influence of this parameter on the absorption after oral uptake. All constituents are salts, they are expected to dissociate into ions after dissolving in the fluids of the gastro-intestinal tract. It is generally thought that ionized substances do not readily diffuse across biological membranes. The substance is found to have skin irritant properties and it is surface active (36.45-53.03 mN/m at 20°C). These properties may enhance absorption when cell membranes are damaged. In addition, based on its surface active properties micelles may be formed, which can enter the circulation via the lymphatic system.

Based on the high water solubility of the mono-ester forms of the main constituents, some absorption after oral intake is expected. In addition, its surface activity and the irritant properties may enhance uptake. On the other hand, the high molecular weight and the ionized state of all constituents is expected to hamper uptake. Therefore, for risk assessment purposes oral absorption of the substance is set at 50%2. The oral toxicity data do not provide reason to deviate from the 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 substance has a vapor pressure of less than 0.5 KPa (2.5 x 10-7 Pa), which indicates a low volatility and exposure to the substance as a vapour is unlikely. Since the substance is a liquid, it is possible that aerosols are formed which can enter the lungs. If the substance reaches the tracheobronchial region, the hydrophilic mono-forms of the different constituents may be retained within the mucus. The high water solubility implies that the substances can dissolve to some extent in the respiratory tract fluids and can be taken up systematically. However, the rate of systemic uptake may be limited by the rate at which the substance partitions out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Those substances remaining in the mucus may be transported out of the deposition region with the mucus and swallowed or may pass across the respiratory epithelium via aqueous membrane pores. As previously mentioned, it was technically not feasible to determine the partition coefficient of the substance. Since it is expected that some components have a high log Pow and others have a low log Pow, the effect of this parameter on the absorption across the respiratory tract epithelium will differ for each component of this UVCB. Furthermore, it is likely that due to the irritant properties of the substance the integrity of the lung epithelium is affected, which will lead to absorption of the substance. Based on the above data, for risk assessment purposes the inhalation absorption of the substance is set at 50%2.

The substance is a liquid which is taken up more easily than dry particulates. Since the water solubility of the mono-forms is relatively high (0.749 g/L (low loading rate) - 3.40 g/L (high loading rate) at 20°C), absorption for these forms is anticipated to be moderate to high. However, the main components of the substance have a molecular weight of slightly under or above 500. Molecules above 500 are not favored for dermal uptake. Based on the structure it is likely that ions will be formed, which can bind to skin components and slow down uptake of the components. Log Pow values between 1 and 4 favour dermal absorption, particularly if water solubility is high. Since it was not technically feasible to determine the Log Pow, it is not possible to determine the effects of this parameter on dermal absorption. As the substance was found to have surface activity, this property will enhance the potential dermal uptake. In addition, the substance is irritant to the skin, and is therefore expected to interfere with the integrity of the epidermal layer. Once the barrier function of the skin compromised, dermal penetration may be enhanced. Taking all aspects in consideration, the dermal adsorption for risk assessment purposes is set at 100%2.

Since there is no partition coefficient available, it is not possible to determine the potential accumulation of the substance in adipose tissue. However, based on its high molecular weight and the limited water solubility and expected lipophilicity of some components present in this UVCB, bioaccumulation can be expected. On the other hand, the chemical structures do not indicate long half-lives of the components after uptake and therefore the potential for bioaccumulation is concluded to be low.



Ref. 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.

Ref. 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

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 50% (oral), 50% (inhalation) and 100% (dermal) for risk assessment purposes.