Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: assessment by an independent expert, operating under GLP and done on the absis of reliable studies, all performed according to OECD protocol or similar under GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline

Results and discussion

Applicant's summary and conclusion

Executive summary:

1.      TOXICOKINETIC ASSESSMENT

A substance can enter the body via the lungs, the gastrointestinal tract, and the skin. To determine the absorption rate, the different routes are assessed individually.

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration (1). Two characteristics of Sodium methallylsulphonate favor uptake via passive diffusion: (a) Sodium methallylsulphonate is highly soluble in water (523 g/L); therefore the substance will dissolve into the gastrointestinal fluids. (b) Sodium methallylsulphonate has a low molecular weight (approximately 158.15) and will easily diffuse. Sodium methallylsulphonate has a log Pow below 0 (< -3.47), which makes it a hydrophilic substance. This characteristic will hamper penetration through lipid membranes. As soon as Sodium methallylsulphonate dissolves in the fluids of the gastro-intestinal tract, it will dissociate into a sodium-ion and a sulphonium-ion. It is generally assumed that ionized substances do not readily diffuse across biological membranes, although the absorption of ionic substances (i.e. acids and bases) is influenced by the varying pH of the GI tract. Since Sodium methallylsulphonate is a sodium salt, it will be fully ionized and absorption will be independent of the pH.

 

For risk assessment purposes oral absorption of Sodium methallylsulphonate is set at 50%, based on its water solubility, its low molecular weight and low Pow and its fast ionic dissociation. 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 low molecular weight. Absorbed Sodium methallylsulphonate is most likely excreted via urine (3). Based on its low partition coefficient (< -3.74), it is very unlikely that Sodium methallylsulphonate will accumulate in adipose tissue.

 

The low vapour pressure (< 1.3 * 10-8 Pa at 20°C) indicates that it is not likely that Sodium methallylsulphonate will reach the nasopharyncheal region or subsequently the tracheo/bronchial/pulmonary region via inhalation of vapour. The particle size is 780.7 µm (volume weighted mean), with 10% of the particles between 10 μm and 339.9 μm, but most (90%) of the particles larger than 1298.5μm. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Therefore only a small fraction of Sodium methallylsulphonate is available for uptake via inhalation, and if inhaled, they are not expected to penetrate deeply into the lung. If Sodium methallylsulphonate reaches the tracheobronchial region, it is likely to dissolve within the mucus lining the respiratory tract and to get absorbed due to its high water solubility and low molecular weight. Based on the above data, for risk assessment purposes the inhalation absorption of Sodium methallylsulphonate is set at 50% (2).

 

Sodium methallylsulphonate is a white powder. When it comes in contact with the skin without additional water, uptake will be limited. However, given the fact that Sodium methallylsulphonate is very soluble, it may dissolve into the surface moisture of the skin.

The first layer of the skin, the stratum corneum, is a barrier for hydrophilic compounds. Sodium methallylsulphonate has a log Pow <–3.74, suggesting that the substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low. Furthermore, the ions formed after Sodium methallylsulphonate has dissolved might influence its adsorption. Especially the sulphonium ion is likely to bind to skin components which would slow the uptake. 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 Sodium methallylsulphonate do not meet the criteria for limited dermal absorption (MW 158), for risk assessment purposes dermal absorption should be set at 100%. However, as it is generally accepted that dermal absorption does not exceed oral absorption, 50% dermal absorption of Sodium methallylsulphonate is considered a realistic dermal absorption factor for risk assessment purposes.

The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

 

 REFERENCES

 

1.     Martinez, 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, May 2008.

3.     A. Parkinson. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics.,, 2001.