3-((3,4-dicyanophenyl)sulfonyl)-N-(2-hydroxypropyl)propane-1-sulfonamide

Endpoint summary

Description of key information

Assessment of toxicokinetic behaviour of the substance derived by expert review of available data as required by section 8.8 of REACH Annex VIII.

Additional information

INFORMATION BASED ON PHYSICO-CHEMICAL PROPERTIES

The assessed substance is phthalonitrile of molecular weight 371.43 g/mol. It is an involatile solid at room temperature and has a melting point of 159.6°C. The substance is essentially insoluble in water (0.214 g/L). The log Pow is – 0.226, suggesting that the substance is of limited solubility in lipids. It is considered to be hydrolytically stable at pH 4 and 7 with an estimated half-life of > 1 year at 25°C. The substance is less hydrolytically stable with an increase in pH, with an estimated half-life of 14.1 days at pH 9. 96.9% of the particles are inhalable (particle size<100 µm microns) and less than 0.02% are respirable (< 5.5 µm).

ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION

ABSORPTION

Given the particle sizes the substance may be inhaled. However, as only 0.02% are classified as respirable, little will reach the alveolus and the great majority will be transferred to the stomach via mucocilliary action and swallowing. The substance undergoes pH specific hydrolysis. At a pH of 4, less than 10% hydrolysis occurred after 5 days at 50°C, equivalent to a half-life greater than 1 year at 25°C. At pH 7 and 9 the estimated half life was estimated to 593 days and 14.1 days, respectively, at 25ºC. Based on these results some limited hydrolysis following oral administration could be expected under the pH conditions encountered in the gastrointestinal tract, which range from ca. pH 1 (stomach) to up to ca. pH 8 (lower intestine).

Considering its relatively low log P value and expected low lipid solubility, it is anticipated that absorption of the intact molecule across the gastrointestinal mucosa will be relatively slow and a significant proportion of an oral dose would be expected to be excreted in the faeces.

No histopathological effects were seen in the study high dose group (1000 mg/kg/bw/day) in either the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test or the Fourteen Day Repeated Dose Oral (Gavage) Range-Finding Toxicity Study. Although this may be because the test substance has very low toxicity it may also indicate that very little of the oral dose of the test substance is absorbed and therefore it is not likely that either the test substance, and/or its metabolites, are able to exert effects on organs and tissues.

There is no information on which to determine for certain whether the test substance can be absorbed significantly via dermal exposure. However, due to the low molecular weight of the substance, it is not possible to fully exclude dermal absorption as a route of exposure.

DISTRIBUTION

It is very unlikely that the substance will exhibit any significant distribution within the body between plasma and tissues considering its low log P value and expected low lipid solubility.

METABOLISM

The susbtance contains a polar hydroxy group which is likely to aid metabolism of the molecule. In a bacterial reverse mutation assay in S. typhimurium and E. coli, the substance did not induce any significant increases in observed numbers of revertant colonies or aberrant cells respectively, either in the presence or absence of metabolising liver S9 mix. Given the negative results, no conclusions about the potential of the substance to undergo metabolic change can be drawn from these studies.

The substance gave a positive result in both a Chromosome Aberration Test in CHL cells and a mouse lymphoma test (both in the presence and absence of S9 metabolic activation). Therefore no conclusion could be drawn regarding the potential of the substance to undergo metabolic change.

EXCRETION

The molecular weight of the substance is slightly above the biliary exclusion limit of circa 325 in the rat and this would favour the elimination of any absorbed substance in the bile. Any such material would most likely return to the intestinal tract for subsequent excretion in the faeces along with any unabsorbed substance. Given the presence of a polar hydroxyl group it is possible that the subsance and/or its metabolites may be excreted via the kidneys into the urine.

CONCLUSION

An assessment of the potential absorption of the substance, based on its physico-chemical properties, suggest that absorption across the gastrointestinal mucosa is likely to be slow and part of an oral dose may be excreted in the faeces. It is possible that a proportion of the substance may be systemically absorbed following oral administration. The substance is likely to be subject to metabolism via a hydroxy group on its structure and this will also aid excretion via the kidneys. Although it is possible that the substance may be systemically absorbed, there is no expectation that it will preferentially distribute to particular organs or tissues in the body.