Sodium dimethyl 5-sulphonatoisophthalate

Endpoint summary

Description of key information

SIM-Ester is considered to be similarly absorbed by the oral and inhalation route.
Dermal penetration is assumed to be very low.
Metabolism is dominated by hydrolyses to the monomethylester and to 5-sulfoisophthalic acid.
Excretion occurs via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

5

Absorption rate - inhalation (%):

50

Additional information

In line with chapter R.7 c (ECHA, 2012) the main toxicokinetic properties of SIM-Ester (CAS-No. 3965-55-7) are assessed on the basis of its physico-chemical properties, the results of the standard toxicity studies performed with this substance and toxicokinetic data available on the structurally related compound dimethylterephthalic acid (DMT). In addition metabolism was elucidated in silico. Specific toxicokinetics or dermal absorption studies are not available for the substance.

 

1. Relevant physico-chemical properties of SIM-Ester

 

Molecular weight: 286.2 g/mol

Physical state: solid (RT)

logPow: -2.86

Water solubility: 32 g/L (20°C)

pKa: -1.34 +/- 0.30 (25°C)

Melting point: 374°C

Particle size distribution: D10: 0.8 +/- 0.1 µm, D50: 5.1 +/- 1.3 µm, D90: 44.7 +/- 29.9 µm

2. Absorption

Oral

Based on its low molecular weight of 286.2 g/mol SIM-Ester is likely to be absorbed in the GI tract since small molecules with a molecular weight below 500 g/mol do favour oral absorption. This assumption is supported by the results of the acute oral toxicity study (Haskell Laboratory for Toxicology and Industrial Medicine (a), 1959). In this study white precipitate in urine was seen at concentrations between 3400 and 11000 mg/kg bw indicating bioavailability after oral dosing. Due to the very good water solubility (32 g/L) and the negative pKa SIM-Ester will readily dissolve into the gastrointestinal fluids. However, absorption by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. This is also in the line with the log Pow value of -2.86 since absorption by passive diffusion generally requires a moderate log Pow value between -1 and 4.

 

Inhalation

Since the melting point of the test item is 374°C it is not expected that SIM-Ester is available for inhalation as vapour. The potential to be inhaled by humans is given if dust particles exhibit an aerodynamic diameter below 100 µm. Particles with an aerodynamic diameter below 50 µm may reach the thoracic region and those below 15 µm the alveolar region of the respiratory tract. Since the particle size distribution (Clariant Produkte (Deutschland) GmbH (d), 2011) of the test substance revealed a median particle size is 5.1 +/- 1.3 µm (D50) a deposition of the substance throughout the respiratory tract including the alveolar region tract can be expected when exposure to dust occurs. Absorption directly across the respiratory tract epithelium by passive diffusion may be likely but limited due to the high water solubility and negative pKa as mentioned above (GI absorption). The results obtained in the acute and subacute inhalation toxicity study (Haskell Laboratory for Toxicology and Industrial Medicine (c), 1959) do not allow a conclusion on inhalation absorption: In both studies rats were exposed to test item dust at the very high concentration of 32 mg/L +/- 20 % (75 % of the particles were≤3 µm). The observed clinical signs were not specific for systemic toxicity. Pathological changes were limited to the lung and most likely attributable to the dust overload phenomenon.

Based on the above information it is concluded that absorption of the substance is comparable after exposure via the oral and inhalation route.  For risk assessment purposes an oral and inhalation absorption of 50% is assumed.

 

Dermal

Based on molecular weight (286.2 g/mol), log Pow (-2.86), pKa (-1.34) and water solubility (32 g/L), the dermal absorption of SIM-Ester is expected to be very low. The substance must be sufficiently soluble in water for partition from the stratum corneum into the epidermis. However, if water solubility is above 10 g/L and the low Pow value below 0 the substance is too hydrophilic to cross the lipid rich environment of the stratum corneum and dermal uptake of these substance will be low. The results of an acute dermal toxicity study in rats (Toxi-Coop Zrt. (b), 2012) do not provide any further information on dermal absorption as no systemic effects were observed at the limit dose of 2000 mg/kg bw. A dermal absorption of 10 % has been reported for dimethylterephthalate (DMT) (OECD, 2001a). In comparison to SIM-Ester DMT is not ionized, much less water soluble (19 mg/L) and has a much higher log Pow (2.25) which favors dermal absorption. This indicates that dermal absorption far below 10% can be expected for SIM-Ester and confirms the initial assumption that dermal penetration of SIM-Ester is very low. For risk assessment purposes the conservative dermal absorption value of 5% is assumed.

 

3. Distribution/Metabolism

In metabolism studies with the structurally related substance DMT the parent compound was basically quantitatively transformed to terephthalic acid in the rat, whereas in mice metabolism resulted in 70 % monomethyl terephthalic acid and 30 % terephthalic acid. The same hydrolytical reactions are expected for SIM-Ester leading to monomethyl-5 -sulfoisophthalate and 5 -sulfoisophthalic acid. This metabolic pathway has been confirmed in silico with the liver metabolism simulator integrated in the OECD QSAR Toolbox.

Due to the high water solubility and low log Pow of SIM-Ester distribution throughout the body via the extracellular aqueous compartment seems likely and a passage of the parent compound or its metabolites through the blood/brain barrier is unlikely.

 

 

4. Excretion

The log Pow of – 2.86, the good water solubility and the molecular weight below 300 g/mol indicated that SIM-Ester has no bioaccumulation potential and that urinary excretion subsequent to metabolism will be the most relevant route of excretion. This has been also show for the DMT which is primarily excreted by the kidney as the monomethylester and terephthalic acid (mouse) or solely as terephthalic acid (rat).

 

5. Generic absorption rates

Based on the above information and due to the fact that there are no specific toxicokinetic data available the generic values of 50 % for oral absorption and inhalation absorption of respirable particles as well as 5 % for dermal absorption were derived.