Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

No ADME studies for SDIBP and the members of hydrotropes were performed. Based on the physico-chemical properties such as molecular weight, water solubility and octanol-water partition coefficient and available toxicological studies, it can be concluded that significant absorption occurs following oral administration while absorption following dermal application is limited. Only one multiple homogeneous layer model was designed on an estimate of dermal penetration for hydrotropes. Dermal penetration simulations based on a mechanistic model of the process of uptake of chemical substances in skin predicts that the dermal penetration of a generic hydrotrope is less than 0.6% of the applied amount. Simulations show that for an exposure extending to 23 hours, the dermal uptake does not exceed 2.8% of the applied amount, regardless of the applied amount (concentration) within the range of 0.0002% to 10%. 10% is considered an upper bound of the concentration of hydrotropes in consumer products. 
Based on this state-of-science modelling, a 2.8% dermal absorption factor can be used as an upper bound value in general population exposure dose calculations for hydrotropes.

Key value for chemical safety assessment

Absorption rate - oral (%):
50
Absorption rate - dermal (%):
2.8
Absorption rate - inhalation (%):
100

Additional information

Toxicokinetic Assessment of SDIBP

SDIBP is a liquid with a high water solubility (353.1 g/L), a low log Kow (-3.11), a moderate vapour pressure (20.94 mbar; 2.094 kPa and Henry’s law constant of 9.65x10-4Pa-m3/mole) with high boiling point (decomposing at 300°C). Its pKa is 6.3. The substance is found to be irritant to the eyes.

SDIPB is composed of benzene (apolar, hydrophobic part) and an anionic sulphonate group accompanied by a counter ion of sodium. It is anionic substance containing both a hydrophilic and a hydrophobic functional group.

No ADME (adsorption, distribution, metabolism and elimination) studies on animal or human for SDIBP and the members of hydrotropeare available. Only one multiple homogeneous layer model was designed on an estimate of dermal penetration for hydrotropes.The data present in this dossier are based on physico-chemical parameters and will allow a qualitative assessment of the toxicokinetic behaviour of SDIBP.

Absorption

 

Oral/GI absorption

 

Following its high water solubility, SDIBP will readily dissolve into the gastrointestinal fluids and subsequently pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

 Based on the physico-chemical properties such as molecular weight (242 g/mole), high water solubility and low octanol-water partition coefficient, it can be concluded that significant absorption occurs following oral administration and the oral absorption by passive diffusion will be favoured, while absorption following dermal application is limited. Substances can be absorbed in the GI tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water.

It is generally thought that ionized substances are poorly lipid soluble and do not readily cross lipid membranes, but they dissolve well in aqueous media. In general, log Kow values between -1 and 4 are favourable for absorption. Nevertheless, a substance with such a log Kow value can be poorly soluble in lipids [the solubility of SDIPB in octanol was 0.273 g/L]and hence not readily absorbed when its water solubility is very low. It is therefore important to consider both, the water solubility of a substance and its log Kow value, when assessing the potential of that substance to be absorbed.

Although SDIBP is an anionic substance, the pKa of SDIBP suggests that this substance will be predominantly in its non-ionized form at physiological pH. The substance can readily diffuse across the biological membranes, but this process might be hampered because of low log Kow.

In the acute oral toxicity study (Huntsman, 2012), no significant effects were noted at the 2000 mg/kg. There were no signs of systemic toxicity. No abnormalities were noted at necropsy. No data are available from repeated toxicity studies by oral administration with SDIBP. However, the 90 day oral study (Huntsman, 1969) has been performed with sodium xylenesulphonate and can be used as source chemical in read-across approach. This study did not determined any measureable adverse effects at 763 mg a.i./kg bw/d. At the end of the experiment (week 14) ten organs of each surviving rat were weighed and examined histologically for pathological changes. Liver enzyme activities were also determined. The overall effects were determined as haematology (decreased red blood cells; decreased activity of a transaminase in serum); urinalysis (decreased specific gravity of urine); organ weights (decreased spleen weight); histopathology (minimal changes in the liver). This indicates that absorption after oral exposure has occurred. In consequence, SDIBP is also considered to be substantially absorbed after oral exposure.

In the gastro-intestinal tract hardly any degradation of the substance is to be expected.

The oral absorption factor is set to 50%, based on the anticipated hampered diffusion of SDIBP as an ionized substance and low Kow value. The results of the toxicity studies do not provide reasons to deviate from this proposed value. 

Respiratory absorption

Given the vapour pressure of 20.94 mbar, SDIBP is not a highly volatile substance and the availability for inhalation as a vapour is limited.

Once in the respiratory tract, the substance may be retained within the mucus, and subsequently absorption may occur. Absorption directly across the respiratory tract epithelium by passive diffusion is favoured in view of the low log Kow value.

 

SDIBP has not toxicity data after inhalation exposure. However, an acute inhalation toxicity study on ammonium xylenesulphonate can be used as read-across data. In this limit test, with an exposure period of 232 minutes, there were no deaths at 6.41 mg/L and half of the exposed animals showed only slight to moderate congestion of the lungs (Conoco, 1980).

 Based on the above considerations, the inhalatory absorption factor is set to 100%, as a worst case assumption.

Dermal absorption

 

For substances with log Pow values <0 and high water solubility (100-10.000 mg/L), poor lipophilicity will limit penetration. If a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, dermal absorption is likely to be low.

In view of its high water solubility (425 g/L) and low log Kow (-3.11), penetration into the lipid-rich stratum corneum and hence dermal absorption might be limited.

No dermal absorption data are available with SDIBP. However, only one multiple homogeneous layer model (Environ, 2010) was designed on an estimate of dermal penetration for hydrotropes and read-across approach is applied to SDIBP. The simulation of this state-of-science modeling showed that the dermal uptake does not exceed 2.8% of the applied amount for an exposure extending to 23 hours, regardless of the applied amount (concentration) within the range of 0.0002% to 10%. The mathematical model simulates the uptake of a chemical substance through the skin into a central sink compartment below the skin. The model uses the substance's diffusion and partitioning coefficients and calculates the total (cumulative) fraction of the substance that enters the stratum corneum for a specific exposure duration. The model does not include any metabolism and the model is believed to represent an upper bound estimate of the potential uptake of the substance through the skin. The differential equations used to describe the model are numerically integrated using MATLAB software. Four exposure scenarios covering the product-relevant ranges of exposure durations and chemical concentrations were modeled to derive exposure-specific uptake percentages. A 2.8% dermal absorption factor can be used as an upper bound value in general population exposure dose calculations for hydrotropes. Therefore, by using read-across data, this value can be used for SDIBP.

 

Distribution

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules, like SDIBP, will diffuse through aqueous channels and pores.

The high water solubility and moderate molecular weight predict that the substance will distribute widely through the body.

Based on the low log Kow, the substance will not likely distribute into cells and hence the intracellular concentration is not expected to be higher than the extracellular concentration.

 

Accumulation

In view of the low log Kow and the high water solubility, SDIBP is not expected to accumulate in the body (lung, adipose tissue, stratum corneum).

 

Metabolism

It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone. Although it is possible to look at the structure of a molecule and identify potential metabolites, it is by no means certain that these reactions will occur in vivo. Once absorbed, SDIBP will undergo oxidation (aromatic hydroxylation) by formation of catechol, followed by rapid conjugation (glycine conjugation, sulfation, or glucuronidation).

Elimination

The kidney, as well as the liver, plays a primary role in the excretion of substances and substance metabolites. In addition to glomerular filtration, the kidney excretes charged substances via carrier-mediated pathways, which are organic anion and organic cation transport pathways, in renal proximal tubular cells. In particular, the organic anion transepithelial transport pathway has been shown to mediate the elimination of anionic substances. Normally, the anion secretory system eliminates metabolites conjugated with glycine, sulfate, or glucuronic acid. Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), high water solubility, and ionization of the molecule at the pH of urine. SDIBP and its metabolites will be mainly excreted via the urine.

References:

-ECHA REACH Guidance on IR & CSA Chapter R.7c: Endpoint specific guidance, November 2012.

-Conti A. and Bickel M. H., History of Drug Metabolism: Discoveries of the Major Pathways in the 19th Century Drug Metabolism Reviews, 6(1), 1-50 (1977).

-http://mededconnect.com/samplechapters/9780323074452/9780323074452.pdf

-Sekine T, Miyazaki H, Endou H,Molecular physiology of renal organic anion transporters.Am J Physiol Renal Physiol 290: F251–F261, 2006.

 

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