Reaction mass of 1,2-Benzenedicarboxylic acid, 4-sulfo-, trisodium salt, 1,2-Benzenedicarboxylic acid, 3-sulfo-, sodium salt (1:3), Sodium sulphate

Endpoint summary

Description of key information

The reaction mass “Reaction mass of 1,2-Benzenedicarboxylic acid, 4-sulfo-, trisodium salt, 1,2-Benzenedicarboxylic acid, 3-sulfo-, sodium salt (1:3), Sodium sulphate” contains as lead structures tri-sodium-3-sulfonatophthalate, tri-sodium-4-sulfonatophthalate and unbound sodium sulphate. Based on the physicochemical properties, it is unlikely that relevant amounts of the two sulfonatophthalate isomers become systemically available following oral exposure and hence they are mainly excreted via the faeces. Dissociated sodium and sulphate ions will be absorbed within the GI tract, further metabolised or incorporated into macromolecules, before being mainly excreted via the kidney in the urine.
Uptake into the systemic circulation following dermal exposure is very limited due to the solid and ionic nature of the reaction mass. Based on the particle size, minor fractions of the reaction mass may be inhaled and can potentially reach the alveolar region, if dust exposure occurs. However, it is not likely that toxicologically relevant amounts will become systemically available.
Neither the sulfonatophthalate isomers nor the respective sodium and sulphate ions have a potential to bioaccumulate within the body.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1 Physico-Chemical Data on Reaction mass of 1,2-Benzenedicarboxylic acid, 4-sulfo-, trisodium salt, 1,2-Benzenedicarboxylic acid, 3-sulfo-, sodium salt (1:3), Sodium sulphate

 

The reaction mass is composed of a mixture of isomers of sodium sulfonatophthalate and sodium sulphate and appears as a white crystalline solid at standard ambient temperature and pressure. The main components tri-sodium-3-sulfonatophthalate and tri-sodium-4-sulfonatophthalate have a molecular weight (Mw) of 312.04 g/mol. Furthermore the reaction mass consists of a significant amount of sodium sulphate which has a of Mw 142.04 g/mol. As the substance is composed of various constituents, the melting point is not clearly determinable. Parts of the substance started to melt between temperatures of 260 and 415°C at standard ambient pressure. Also the boiling point could not be determined as the substance started to decompose at higher temperatures. The reaction mass has a very low vapour pressure which can be regarded as negligible for the present assessment. Particle size measurements determined that approximately 94.02 % of the crystals are smaller than 100 µm, 5.73 % are smaller than 10 µm and 1.57 % are smaller than 4 µm. The substance is very well water soluble as indicated by the measured water solubility value of 285 g/L at 20°C. Due to the ionic nature of the constituents the LogPow is estimated to be < -1.2 at 20°C. When the isomers of sodium sulfonatophthalate are placed in an aqueous solution, the respective ions are formed rapidly. Similarly, sodium sulphate will readily dissociate in the sodium and sulphate ions. Hydrolysis of the constituents itself is not expected.

 

2Reaction mass of 1,2-Benzenedicarboxylic acid, 4-sulfo-, trisodium salt, 1,2-Benzenedicarboxylic acid, 3-sulfo-, sodium salt (1:3), Sodium sulphate

 

Absorption

 

Oral route:

Within the gastrointestinal (Gl) tract, the ionic nature, the high water solubility and low LogPow of the sulfonatophthalate isomers will drastically limit an uptake into the systemic circulation via passive diffusion. Although it cannot be ruled out completely, absorption with bulk transport of water is unlikely because of the Mw of the isomers (i.e., > 200 g/mol).

The sodium ions, which dissociate from the sulfonatophthalate isomers and from sodium sulphate will be efficiently absorbed through the walls of the GI tract by active transport processes.

Compared to the sodium ions, the sulphate ion will be less efficiently absorbed following oral administration (Florinet al., 1991). The absorption efficiency increases with the amount of sulphate ingested (Bauer, 1976; Morris and Levy, 1983) while the upper GI tract appears to be mainly responsible for site for sulphate absorption (Florinet al.,1991). 

With regards to toxicological data, in an acute oral systemic toxicity study in rats (OECD 423), the LD50 value for the reaction mass was determined to be higher than 2000 mg/kg bw (limit dose) with no local or systemic effects noted. Furthermore, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (OECD 422) was conducted with the reaction mass. In this study no adverse effects were observed and the NOAEL for general and reproductive toxicity was determined to be 1000 mg/kg bw/day (limit dose).

Overall, while absorption of the sulfonatophtalate isomers is expected to be very limited, the respective sulphate and sodium ions will readily become bioavailable. Considering the absence of systemic effects in the toxicological investigation and the fact that sodium and sulphate occur naturally within the body, it is unlikely that toxicological relevant amounts of the reaction mass will reach the systemic circulation.

Inhalation route:

Considering the particle size distribution, it cannot be ruled out that minimal fractions of the substance are inhalable if dust exposure occurs. However, the hydrophilic sulfonatophthalate isomers will be retained in the mucus and thus are not available for systemic absorption. Moreover, due to the fact that sodium and sulphate occur naturally within the body it can be ruled out that toxicological relevant amounts will reach the systemic circulation via the inhalation route.

Dermal route:

The physicochemical properties of the isomers of sodium sulfonatophthalate and sodium sulphate do not favour dermal absorption. As the reaction mass is a solid at room temperature, it has to dissolve into the surface moisture of the skin before any potential uptake can take place. Once dissolved, the ionic nature of the constituents will drastically hinder dermal uptake.

The assumption that no dermal absorption occurs is further strengthened by the results achieved from the dermal toxicity testing. In an acute dermal toxicity study, thereaction massdid no cause any local or systemic effects and the LD50 was determined to be greater than the limit dose (2000 mg/kg bw).

Overall, the physicochemical properties and the findings from the dermal toxicity studysupport that no absorption into the systemic circulation is expected after dermal application.

 

Distribution and metabolism

 

Based on the physicochemical properties, it is unlikely that relevant amounts of the sulfonatophthalate isomers become systemically available. However, in case a certain amount of the substance enters the systemic circulation, bioaccumulation within the body tissues is unlikely considering the substances’ physicochemical properties.

With regards to sodium and sulphate, systemic distribution can be assumed as both compounds are normal constituent of human blood and do not accumulate in tissues. Sodium is naturally used in all body tissues for a range of physiological processes.Sulphate is used during the biotransformation of several compounds (Morriset al.,1984) and can be biosynthetically incorporated into other macromolecules such as glycoproteins, glycosaminoglycans, and glycolipids (Morris and Sagawa, 2000). Unboundsulphates are regulated by the kidney through re-absorption mechanism (Morris and Levy, 1983; Cole and Scriver, 1980)

 

Excretion

 

Following oral intake it is expected that the vast majority of the ionised sulfonatophthalate isomers will be readily excreted via the faeces.

Residual sodium will naturally be excreted with the urine.Sulphates, in unbound form or as conjugates of various substances, are ultimately eliminated from the blood via the kidneys and will be excreted with the urine. At high sulphate doses that exceed intestinal absorption, sulphate is excreted in faeces.

 

3 Summary

 

The reaction mass “Reaction mass of 1,2-Benzenedicarboxylic acid, 4-sulfo-, trisodium salt, 1,2-Benzenedicarboxylic acid, 3-sulfo-, sodium salt (1:3), Sodium sulphate” contains as lead structures tri-sodium-3-sulfonatophthalate, tri-sodium-4-sulfonatophthalate and unbound sodium sulphate. Based on the physicochemical properties, it is unlikely that relevant amounts of the two sulfonatophthalate isomers become systemically available following oral exposure and hence they are mainly excreted via the faeces. Dissociated sodium and sulphate ions will be absorbed within the GI tract, further metabolised or incorporated into macromolecules, before being mainly excreted via the kidney in the urine.

Uptake into the systemic circulation following dermal exposure is very limited due to the solid and ionic nature of the reaction mass. Based on the particle size, minor fractions of the reaction mass may be inhaled and can potentially reach the alveolar region, if dust exposure occurs. However, it is not likely that toxicologically relevant amounts will become systemically available.

Neither the sulfonatophthalate isomers nor the respective sodium and sulphate ions have a potential to bioaccumulate within the body.

 

4 References

 

Bauer JH. (1976) Oral administration of radioactive sulphate to measure extracellular fluid space in man. Journal of Applied Physiology 40:648-650.

 

Bonse G., Metzler M. (1978) Biotransformation organischer Fremdsubstanzen. Thieme Verlag, Stuttgart.

 

Cole DEC, Scriver CR. 1980. Age-dependent serum sulfate levels in children and adolescents.

Clinica Chimica Acta 107:135-139.

 

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

Florin T., Neale G., Gibson G.R., Christl S.U., Cummings JH. (1991) Metabolism of dietary

sulphate: Absorption and excretion in humans. Gut 32:766-773.

 

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press,,, 2nd Edition 688-689.

 

Morris ME, Galinsky RE, Levy G. 1984. Depletion of endogenous inorganic sulfate in the

mammalian central nervous system by acetaminophen. Journal of Pharmaceutical Sciences 73:853.

 

Morris M.E, Levy G. (1983) Serum concentration and renal excretion by normal adults of

inorganic sulfate after acetaminophen, ascorbic acid, or sodium sulfate. Clinical Pharmacolgy and Therapeutics 33:529-536.

 

Morris M.E., Sagawa K. (2000) Molecular mechanisms of renal sulfate regulation. CRC Critical Reviews in Clinical Laboratory Medicine. 37(4):345-388.

 

Mutschler E., Schäfer-Korting M. (2001) Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart.

Rozman K.K., Klaassen C.D. (1996) Absorption, Distribution, and Excretion of Toxicants. In Klaassen C.D. (ed.) Cassarett and Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill, New York.