sodium 3-[(2,3-dicyanophenyl)thio]propane-1-sulfonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

other: Not assignable as result is from expert assessment

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This read-across is based on the hypothesis that the Source and Target substances will have similar toxicological and ecotoxicological properties due to their close physical-chemical and structural similarities. For example, both the Source and Target substances are monoconstituents which share structural similarities and contain the same functional groups (thio ether, sulfonate, vicinal nitrile groups).

Data source

Reference

Reference Type:

other: Internal Company Report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Assessment of toxicokinetic behaviour of the substance derived from available data as required by REACH Annex VIII section 8.8

Deviations:

not applicable

Principles of method if other than guideline:

Expert review.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Automatically generated during migration to IUCLID 6, no data available

IUPAC Name:

Automatically generated during migration to IUCLID 6, no data available

Test material form:

other: Study undertaken as expert review of available data which is based on the test material in powder form.

Results and discussion

Any other information on results incl. tables

INFORMATION BASED ON PHYSICO-CHEMICAL PROPERTIES

The source material is a lithium salt of a phthalonitrile derivative with a molecular weight 288 as the lithium salt. It is an involatile solid at room temperature and has a melting point of 237.9°C and decomposes before boiling at 260°C. The substances water solubility is 293.2 g/l, while the log P_owis -2.32, suggesting that the substance is of very limited solubility in lipids.

 

In its solid form the source material is a lumpy solid of which 30.4% of the particles are inhalable (particle size <100 µm) and 0.115% are respirable (particle size < 5.5 µm).

 

The source material is hydrolytically stable at pH 4 and pH 7 at 50°C giving an estimated half-life of > 1 year at 25°C, however, at pH 9 it undergoes rapid hydrolysis with a half-life of 9.9 days at 50°C to produce three hydrolysis products.These were inferred to be structurally similar to the source material, with two of the hydrolysis products likely to be isomers of each other, while one product was believed to consist of two species.

 

 

ABSORPTION, DISTRIBUTION AND EXCRETION

 

 

Absorption

Potential for Absorption

As a proportion, around 30% of the source material in solid form could be inhaled following exposure to airborne dusts, however, given the particle size very little will reach the alveoli and the great majority will be transferred to the stomach via mucocilliary action and swallowing.

 

The source material is a relatively low molecular weight molecule and therefore its size is unlikely to present a significant barrier to absorption across the gastrointestinal mucosa, hence, uptake as it passes through the gastrointestinal tract may occur. However, uptake is likely to vary as it passes through the gut given that it will be ionised to differing degrees at the different pHs encountered in the gastrointestinal tract. The source material has a very low log P value and therefore the unionised form is likely to be inhibited from passage across membranes due to a lack of lipid solubility. It is unlikely that active transport mechanisms will be a significant uptake route due to a lack of similarity with endogenous molecules; however, the source test material is a salt and will release lithium ions which will compete with sodium ions for uptake via sodium pumps. 

 

Overall, it can be expected that absorption of the intact molecule across the gastrointestinal mucosa will occur, but a proportion of an oral dose is likely to not be absorbed and subsequently be excreted in the faeces.

 

The source material undergoes limited hydrolysis at pHs of 4 and 7 with less than 10% hydrolysis occurring after 5 days at 50°C, equivalent to a half-life greater than 1 year at 25°C. However, at pH 9 after 5 days at 50 °C approximately 30% hydrolysis occurs. Based on the hydrolysis results, it is possible that at least a degree of hydrolysis of the source material following oral administration might occur in the lower intestine where up toca.pH 8 could be encountered.

 

Given the structural similarity of the main hydrolysis components to the source test material it is expected that they will have a similar absorption profile to the parent molecule.

 

 

Evidence for Absorption

Histopathological effects were seen in the kidneys at 300, 500 mg/kg/bw/day and in the spleen at 30, 300 and 500 mg/kg/bw/day in the repeated dose reproductive developmental toxicity screening study. Additionally, there was reduction in implantation sites and thus litter size in the study at 300 and 500 mg/kg/bw/day. These observations provide clear evidence that a proportion of the oral dose of the source material is indeed absorbed and that either the source material, and/or its metabolites/hydrolysis products are achieving concentrations at which they can exert effects.

 

There is no information on which to determine for certain whether the source test material can be absorbed significantly via dermal exposure. Given its molecular weight it is conceivable that a dermal absorption could occur; however, factors such as it low lipid solubility are likely to mean that absorption by this route is unlikely to be significant.

 

 

DISTRIBUTION

It is very unlikely that the source test material will exhibit any significant distribution within the body between plasma and tissues. The source material is a salt and on dissolution will form an anion and a lithium cation. The anion is polar and therefore it is unlikely to distribute to any significant extent in the body. The lithium cation is likely to compete with sodium and ultimately the lithium ions are likely to be incorporated into the body sodium pool. If not replenished, the lithium will be lost over time via normal excretion processes.

 

With regards to the reduction in implantation sites in the repeated dose/reproductive developmental toxcity screening study, within the confines of the study it was not possible to confirm if the source material and/or its metabolites were exerting a direct effect on embryos and/or the implantation process, or if the implantation reduction was due to a secondary effects from maternal toxicity. 

 

 

METABOLISM

The source material contains a water soluble sulphonic acid and two cyano groups which are likely to aid metabolism of the molecule by cytochrome P450 enzyme metabolising system. The sulphonic acid group is also likely to aid excretion of the molecule.

 

In a bacterial reverse mutation assay using S. typhimurium and E. coli , an in vitro mammalian chromosome aberration assay and an in vitro mouse lymphoma assay, the source test material 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 source material to undergo metabolic change can be drawn from these studies.

 

  

EXCRETION

The main route of excretion of absorbed source test material and/or its metabolites is likely to be via the kidneys into the urine. Histopathological changes observed in the kidneys suggest that it and/or its metabolite(s) are present in these organs after exposure. 

 

The molecular weight (as the free acid) of the source material is below the biliary exclusion limit of circa 325 in the rat and 500 in humans and therefore elimination of any absorbed substance in the bile is not expected to be significant. 

 

 

The lithium ions from the test material can be expected to be excreted in urine.

 

CONCLUSION

An assessment of the potential absorption of the source material based on its physico-chemical properties suggest that absorption across the gastrointestinal mucosa may occur, although part of an oral dose can be expected to be excreted in the faeces. The observation of histopathological changes in the kidneys and spleen, along with reduced litter size in a repeated dose reproductive developmental toxicity screening study confirm that systemic absorption of an oral dose can occur.  

 

Systemically, absorbed source test material is likely to be subject to metabolism via sulphonic acid and cyano groups on its structure. Ultimately, it is expected to be excreted via the kidneys. There is no expectation that the source material will preferentially distribute to particular organs or tissues in the body.

 

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: No bioaccumlation based on expert review of available data.
The source substance will be systemically absorbed but likely to be subject to metabolism via sulphonic acid and cyano groups on its structure. Ultimately, it is expected to be excreted via the kidneys. There is no expectation that the source susbstance will preferentially distribute to particular organs or tissues in the body.

The Source substance has a comprehensive data set generated for a REACH Annex VIII registration and this along with its similarity to the Target substance are consider sufficient to consider the read-across an appropriate adaptation to the standard information requirements of Annex VII of the REACH regulation for the Target substance in accordance with the provisions of Annex XI, 1.5 of the REACH regulation. Please see the attached document in the Background Material section for further details on the justification of the read across approach.

Executive summary:

Introduction

An expert review of the toxicokinetic profile of the source material was assessed based on physicochemical profile and available toxicity data. The results of this review are being used as read across to provide toxicokinetic info on the target submission substance. This read-across is based on the hypothesis that the Source and Target substances will have similar toxicological and ecotoxicological properties due to their close physical-chemical and structural similarities. For example, both the Source and Target substances are monoconstituents which share structural similarities and contain the same functional groups (thio ether, sulfonate, vicinal nitrile groups).

Results and Conclusion

An assessment of the potential absorption of the source material based on its physico-chemical properties suggest that absorption across the gastrointestinal mucosa may occur, although part of an oral dose can be expected to be excreted in the faeces. The observation of histopathological changes in the kidneys and spleen, along with reduced litter size in a repeated dose reproductive developmental toxicity screening study confirm that systemic absorption of an oral dose can occur.

Systemically, absorbed source test substance is likely to be subject to metabolism via sulphonic acid and cyano groups on its structure. Ultimately, it is expected to be excreted via the kidneys. There is no expectation that the source material will preferentially distribute to particular organs or tissues in the body.  

The Source substance has a comprehensive data set generated for a REACH Annex VIII registration and this along with its similarity to the Target substance are consider sufficient to consider the read-across an appropriate adaptation to the standard information requirements of Annex VII of the REACH regulation for the Target substance in accordance with the provisions of Annex XI, 1.5 of the REACH regulation. Please see the attached document in the Background Material section for further details on the justification of the read across approach.