[No public or meaningful name is available]

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Theoretical assessment

Adequacy of study:

key study

Study period:

07 October 2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP assessment report based on expert judgement

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

An expert assessment was made based on all data available.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N1,N3‐bis(3‐methylphenyl)‐5‐[(3‐methylphenyl)sulfamoyl]benzene‐1,3‐dicarboxamide

Molecular formula:

C29H27N3O4S

IUPAC Name:

N1,N3‐bis(3‐methylphenyl)‐5‐[(3‐methylphenyl)sulfamoyl]benzene‐1,3‐dicarboxamide

Test material form:

solid: particulate/powder

Details on test material:

- Appearance: Off-white powder
- Storage condition: At room temperature protected from light

Test animals

Species:

other: none

Administration / exposure

Route of administration:

other: Oral, dermal and inhalation

Vehicle:

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. Pergafast 425 has a relatively high molecular weight (513.6), which will limit passage through biological membranes. Pergafast 425 shows low water solubility of 0.00474 mg/L and a high partition coefficient (Log Pow: 4.3) which makes the substance not favorable for absorption by the GI-tract via passive diffusion.
However, the substance could be taken up via micellular solubilization by bile salts and uptake via the lymphatic system or transport via pinocytosis. Based on these physicochemical properties of Pergafast 425, a moderate uptake by the GI-tract is anticipated, and for risk assessment purposes the oral absorption of Pergafast 425 is set at 50%. The results of the toxicity studies do not provide reasons to deviate from the proposed oral absorption.
For inhaled substances the process of deposition of the substance on the surface of the respiratory tract and the actual absorption have to be differentiated. Pergafast 425 has a low vapour pressure (20°C: < 8.4 x 10-7 Pa) and was found to decompose before a boiling point was reached, which indicates that the substance is not very volatile and exposure to the substance as a vapour is unlikely. Pergafast 425 is a powder. Since 90% of the particles is smaller than 55.0 μM, the largest part of the substance has the potential to be inhaled and may reach the thoric region. Furthermore, 50% is smaller than 12.9 μM, which means that at least 50% of the substance may reach the alveolar region of the respiratory tract. If these particles reach these regions, Pergafast 425 is likely to be taken up via micellular solubilization.
Therefore, it is concluded that for risk assessment purposes the inhalation absorption of Pergafast 425 is set at 100%.

As Pergafast 425 is a powder, uptake through the skin is unlikely to occur unless it is dissolved in a body fluid (sweat). Pergafast 425 is poorly soluble in water (below 1 mg/L), therefore is the partition from the stratum corneum into the epidermis is expected to be limited. Its ability to dissolve in lipids will favour uptake into stratum corneum. Its high molecular weight makes the substance not favourable for dermal uptake. According to the guidance2, a default value of 10% skin absorption is used when the molecular mass is above 500 and log Pow is outside the range [-1, 4]. Since the substance has a molecular weight of 513.6 and a log Pow of 4.3, it those meet both criteria and the dermal absorption of Pergafast 425 for risk assessment purposes is thus set at 10%. The dermal toxicity data do not provide reason to deviate from the proposed dermal absorption factor.
Generally, substances with a high log Pow value have long biological half-lives. Daily exposure to substances with a log Pow of around 4 or higher could result in a buildup of that substance within the body. Pergafast 425 showed a BCF below 100, which indicates a low bioaccumulation potential. Therefore, the bioaccumulation potential of Pergafast 425 is expected to be low.

REFERENCES
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

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 50% (oral), 100% (inhalation) and 10% (dermal) for risk
assessment purposes. The bioaccumulation potential is expected to be low.