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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Theoretical assessment taking all currrently 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.
Qualifier:
according to
Guideline:
other: Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency
Version / remarks:
Version 2.0 November 2014
GLP compliance:
no
Type:
absorption
Results:
For risk assessment purposes, 50% is used for oral, and 100% for dermal and inhalation absorption

A substance can enter the body via the gastrointestinal tract, the lungs, and through the skin. In general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration (1). After oral intake, two characteristics of MTBAC favor uptake via passive diffusion (passage of small water-soluble molecules through aqueous pores or carriage of such molecules across membranes with the bulk passage of water): (a) MTBAC is highly soluble in water (> 1 * 103g/L), therefore the substance will readily dissolve into the gastrointestinal fluids to allow direct uptake; (b) MTBAC has a moderate molecular weight (approximately 236), and small molecules can be taken up via diffusion. On the other hand, MTBAC will not easily dissolve in lipids, as reflected in its log Pow below 0 (log Pow = -2.0). Its lipophobic character will hamper penetration through lipid membranes. Furthermore, MTBAC dissociates in aqueous solution to render a chloride ion and a methyltributylammonium ion. It is generally assumed that ionized substances do not readily diffuse across biological membranes. Based on these two factors hampering penetration (lipophobicity and ionicity), oral absorption of MTBAC is set at 50% for risk assessment purposes (2). The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor. Once absorbed, wide distribution of the test substance throughout the body is expected based on its high water solubility and moderate molecular weight. Absorbed MTBAC is most likely excreted via urine (3). Based on the low partition coefficient, MTBAC is not expected to bioaccumulate significantly in adipose tissue. The vapour pressure of MTBAC was found to be low (7.0 * 10-3 Pa at 25°C), which indicates that the substance is not available for inhalation as a vapour. However, MTBAC is marketed in aqueous solution. This might lead to the formation of aerosols, which may be inhaled and enter the respiratory tract. Once MTBAC reaches the tracheobronchial region, the substance is likely to dissolve within the mucus lining of the respiratory tract and to get absorbed due to its high water solubility and moderate molecular weight. Based on the above data, for risk assessment purposes the inhalation absorption of MTBAC is set at 100%.Exposure to MTBAC will be considered in aqueous solution. Dermal uptake is facilitated by this liquid form. The first layer of the skin, the stratum corneum, is a barrier for hydrophilic compounds. Based on its hydrophilic nature, crossing the first layer of the skin, the stratum corneum, is expected to be hampered. Moreover, its ionic state might influence penetration as the quaternary ammonium ion can bind to skin components which would further slow uptake (2). On the other hand, MTBAC is a skin irritant. This implies that exposure of the skin will affect the skin integrity, resulting in dermal uptake of MTBAC. The moderate molecular weight and high water solubility of MTBAC are favourable for dermal absorption. According to the criteria given in the REACH Guidance (2), 10% dermal absorption will be considered in case MW >500 and log Pow <-1 or >4, otherwise 100% dermal absorption should be used. As the physical/chemical properties of MTBAC do not meet the criteria for limited dermal absorption (MW 236; log Pow = -2), for risk assessment purposes dermal absorption is set at 100%. This implies that dermal absorption exceeds oral absorption, which is a direct consequence of the skin irritating properties of MTBAC. Based on the above data, for risk assessment purposes the dermal absorption of MTBAC is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor. 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 2.0 November 2014. 3. Parkinson. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill, New York, 2001.

Conclusions:
Based on evaluation of all available data, for risk assessment purposes 50% absorption is used for oral, and 100% for dermal and inhalation absorption.

Description of key information

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 100% (dermal) for risk assessment purposes. MTBAC is not expected to bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information