Reaction mass of Ammonium bisethanedioato bisaquo niobate(V) (anhydrous form) and Ammonium hydrogen ethanedioate ethanedioic acid (anhydrous form)

Endpoint summary

Description of key information

No studies are available. Based on molecular structure, molecular weight, water solubility, and octanol-water partition coefficient it can be expected that after oral absorption the oxalate and ammonium components of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate are absorbed. Systemic availability after inhalation is not expected and due to its skin sensitising properties, dermal uptake of at least a small fraction of applied doses is expected. Based on the toxicological profile of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate, oxalic acid/oxalate is considered to be the relevant component. Oxalic acid/oxalate is not metabolised and the renal pathway is the relevant route of excreteion. The bioaccumulation potential is expected to be low.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

There are no data available investigating the toxicokinetic behaviour of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate. However, assessment is based on the chemical structure, physico-chemical properties and information gathered from (toxicological) studies with Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate.

 

Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is a multi-constituent substance, consisting of

1. Ammonium oxobis(ethanedioato) bisniobate(V) hydrates and

2. Ammonium hydrogen ethanedioate ethanedioic acid dehydrate.

 

Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is a solid with a mean mass median aerodynamic diameter (MMAD) of 76.2 µm. The vapour pressure is 0.00028, 0.00043, or 0.0032 hPa at 20, 25, or 50 °C, respectively. Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is highly water soluble under acidic conditions with 325 g/L at pH 0.43 and the n-octanol/water partition coefficient is -5.12 at 20°C. Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is not surface active.

 

Absorption of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate after oral exposure:

After ingestion or oral instillation of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate, the test material will be exposed to the acidic environment of the stomach (approximately pH 0-2, depending on dietary status).

Constituent 2 is likely to be dissolved into the individual components, which is why the following consideration will focus on the individual components rather than the second constituent as a whole:

Ammonium was shown to be absorbed via the upper and the lower part of the gastrointestinal tract and is easily transferred into the circulation (Evans et al., 1966).

 

Oxalic acid is a relative strong organic acid, which is moderately soluble in water (Hodkinson and Zarembski, 1968). Approximately 2-5% of oxalic acid is absorbed via the gastrointestinal tract. Absorption is influenced by microbial degradation in the intestine, but also by the dietary concentration of calcium, as insoluble calcium oxalate is formed, which cannot be transferred across the intestinal mucosa. There is hardly any information available on the mechanism of intestinal absorption of oxalic acid. However, as the intestinal concentration clearly exceeds the blood concentration, diffusion of free oxalate ions down an electrochemical gradient is likely. Apart from gastrointestinal absorption, metabolism of ascorbic acid and glycine is known to be an endogenous source for oxalic acid under physiological conditions (Hodkinson and Zarembski, 1968).

 

Constituent 1 is a chelate complex of two oxalate molecules with one Nb(V) as central atom. The complex is negatively charged with ammonium as counter ion. As shown in the available water solubility study (Wild, C., 2013), the registered substance is highly water soluble under acidic conditions (325 g/L at pH 0.43 and 20°C). The toxicokinetic behaviour of ammonium was briefly described above, thus, the following consideration will focus on the niobium complex:

After ingestion or oral instillation, the test material will be exposed to the acidic environment of the stomach (approximately pH 0-2, depending on dietary status). As mentioned above, the test material will dissolve and the complex will exist in its ionic state. It is questionable, whether the complex will be hydrolysed under this acidic condition. If so, formation of insoluble niobium(V) hydroxide is expected (Anonymous, 2014). This should have led to precipitation in the water solubility study; however, there was no precipitation reported (Wild, C., 2013). It can thus be assumed that the niobium complex of constituent 1 is hydrolytically stable under the acidic gastric conditions.

After passing the stomach, the niobium complex will reach the intestine. Again it is questionable whether the complex will be hydrolysed or, alternatively, suffers microbial degradation. It was reported that microbial degradation might occur under certain circumstances (Anonymous, 2014). However, again niobium(V) hydroxide is expected to be formed in this case, which is not water soluble. Consequently, even if the niobium oxalate complex is degraded by the intestinal flora, the resulting niobium(V) hydroxide would precipitate and is therefore unlikely to be absorbed via the intestinal mucosa (ECHA, 2012). In case the niobium oxalate complex will remain unaffected, absorption is unlikely as the complex is ionised and absorption by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid (ECHA, 2012). Based on the molecular weight of >200 g/mol, the complex is considered to be too large to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water (ECHA, 2012). Together with the partition coefficient of -5.12 at 20 °C, bioavailability of the niobium moiety after oral exposure to Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is unlikely.

 

In summary, only ammonium and oxalic acid/oxalate are considered to be bioavailable after oral exposure, whereas the niobium oxalate complex is considered to be not absorbed via the gastrointestinal tract. This is in line with the fact that the only toxicologically relevant effects of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate noted in repeated dose toxicity studies via the oral route (CBMM Europe BV, Key, 2014, RDT and CBMM Europe BV, Key, 2020, RDT) were renal and urinary bladder changes in high dose animals (311 mg/kg bw/day), which are contributed to deposition of calcium oxalate rather than the niobium containing moiety.

 

Absorption of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate after inhalation exposure:

Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is unlikely to be absorbed via the respiratory tract, as the vapour pressure is very low (0.00043 hPa at 25°C) and the particle size (mean MMAD 76.2 µm) is small enough to be inhalable, but too big to reach the alveolar region (ECHA, 2012). Additionally, the partition coefficient of -5.12 at 20 °C is too low to favour absorption across the respiratory tract epithelium (ECHA, 2012). Together with the fact that there was no sign of systemic toxicity noted in the acute inhalation toxicity study (CBMM Europe BV, Key, 2014, AIT), bioavailability after inhalation exposure is considered unlikely.

 

Absorption of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate after dermal exposure:

Based on the physical state (solid), the partition coefficient (-5.12 at 20 °C), and the fact that Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is not corrosive to the skin (CBMM Europe BV, Key, 2011, OECD 404), absorption via the dermal route is unlikely. This is further supported by the absence of any systemic toxicity after dermal application (CBMM Europe BV, Key, 2006, ADT). However, based on the skin sensitising potential (CBMM Europe BV, Key, 2014, LLNA), some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2012).

 

Distribution, metabolism and excretion of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate

As described above, absorption of oxalate/oxalic acid and ammonium after oral exposure is of major toxicological relevance. Due to the fact that the niobium oxalate complex is unlikely to be absorbed and expected to be excreted via faeces without further conversion and that there is no information available on systemic toxicity of the niobium oxalate complex, the following discussion will focus on ammonium and oxalic acid/oxalate only.

 

Ammonium is submitted to the urea cycle, which is located in the liver. The nitrogen is used to build up non-essential amino acids. Finally, excess ammonium is excreted via urine, resulting in net acid loss.

 

Oxalic acid is widely distributed in the body as it is present in all body tissues albeit at normally very low concentrations. Oxalic acid was found in higher concentrations in whole blood as compared to plasma alone, suggesting that it is predominantly located in red blood cells (Hodkinson and Zarembski, 1968). This is in line with the fact that 1) oxalic acid is not favourable for binding to plasma proteins and 2) most biological membranes are permeable for oxalic acid (passive diffusion). Tissue concentrations vary significantly, with the highest values being observed for the kidney and the lowest concentration reported for the brain (Hodkinson and Zarembski, 1968).

There is no evidence that oxalic acid undergoes biotransformation in mammals, except for degradation observed in intestinal microbial flora. However, the reaction with calcium under formation of insoluble crystals at physiological pH is of biological relevance (Hodkinson and Zarembski, 1968).

Even though a small fraction of oxalic acid may be excreted via bile followed by microbial degradation in the intestinal lumen, Hodkinson and Zarembski (1986) concluded that the renal pathway is of most biological relevance. Oxalic acid is excreted unchanged in the urine, with 88-99% of intravenously administered radiolabelled material having been recovered in the urine within 36 h (Elder and Wyngaarden, 1960, as cited in Hodkinson and Zarembski, 1968). However, urinary excretion of oxalic acid usually does not exceed 40 mg per day in adults, with the rate of excretion varying between day and night and reaching a maximum approximately 3 h after having a meal (Hodkinson and Zarembski, 1968). Other than for weaker organic acids, renal excretion of oxalic acid is unaffected from alkalinity or basicity of the urine, but is increased during water diuresis. It was reported that oxalate is filtered at the renal glomerulus, but more than 90% is apparently reabsorbed by passive back-diffusion in the tubules (Hodkinson and Zarembski, 1968). A direct relationship between renal excretion of oxalic acid and calcium was noted in man and it was suggested that undissociated calcium oxalate is reabsorbed less readily than the oxalate ion itself in the renal tubule. Urinary oxalic acid is present either as ionised form or in complexes with magnesium or other cations. Only a relatively small fraction is bound to urinary proteins or peptides. However, urine is generally supersaturated with respect to calcium oxalate. Even though this condition is stabilised by the presence of urea and various ions such as citrate, magnesium, lactate, sodium, potassium and sulphate, crystallisation is commonly seen for calcium oxalate. Calcium oxalate is the most common constituent of renal calculi, occurring in approximately 2/3 of all stones (Hodkinson and Zarembski, 1968). Stones formed in kidneys of humans and rats are identical in crystalline - and matrix composition, as well as location (renal papillary surface). Apart from this, it is interesting that for both rats and humans testosterone seems to play an important role in calcium oxalate based renal calculi formation, as males are more prone to calcium oxalate nephrolithiasis for both rats and humans (Kahn, S.R., 1997). Apart from crystallisation in the kidneys, calcium oxalate was further reported to deposit in any tissue (i.e. among others, in thyroid, retina, and at the walls of blood vessels) due to high concentration in the body fluid and elevation of the ionic product of calcium oxalate. Deposition is often associated with inflammation and fibrosis, e.g. in the renal parenchyma and myocardium (Hodkinson and Zarembski, 1968).

In summary, oxalate is widely distributed within the body fluid and predominantly excreted via the renal pathway. Once absorbed via the gastrointestinal tract, oxalate will not undergo metabolism, but association with calcium and consequently precipitation is generally known for oxalate.

 

In conclusion, based on molecular structure, molecular weight, water solubility, and octanol-water partition coefficient it can be expected that after oral absorption the oxalate and ammonium components of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate are absorbed. Systemic availability after inhalation is not expected and due to its skin sensitising properties, dermal uptake of at least a small fraction of applied doses is expected. Based on the toxicological profile of Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate, oxalic acid/oxalate is considered to be the relevant component. Oxalic acid/oxalate is not metabolised and the renal pathway is the relevant route of excretion. The bioaccumulation potential is expected to be low.

 

 

References:

- Anonymous (2014) Biodegradation test of ANO. Koei Techno Company, limited, Sodegaura-city, Japan. Report No. B12011.

- ECHA (2012) Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance (Version 1.1).

- Evans, W. B.; Aoyagi, T.; Summerskill, W. H. (1966) Gastrointestinal urease in man. II. Urea hydrolysis and ammonia absorption in upper and lower gut lumen and the effect of neomycin. Gut 7(6):635-639.

- Hodgkinson. A.; Zarembski, P. M. (1968) Oxalic Acid Metabolism in Man: A Review. Calcif Tissue Res. 2(2):115-32.

- Kahn, S.R. (1997). Animals models of kidney stone formation: an analysis. World J Urol 15:236-243.

- Wild, C. (2013) Report Amendment No. 1 to Study S12-3638 Water Solubility of Ammonium Niobium Oxalate. Eurofins Agroscience Services EcoChem GmbH, Niefern-Oeschelbronn, Germany, Report No. S12-03638.