Dipotassium oxalate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

expert statement

Type of information:

other: expert statement based on physico-chemical properties

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: According to Endpoint Specific Guidance Chapter R.7c, Version 3.0 - June 2017 and Regulation (EU) No. 1907/2006 (REACH) section 8.8.1 one should perform “assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information". Thus, "the standard information requirements of REACH for substances manufactured or imported in quantities of ≥1 ton (see Annex VII of the respective regulation), include mainly physico-chemical (PC) data, and data like skin irritation/corrosion, eye irritation, skin sensitization, in vitro mutagenicity, acute oral toxicity, short-term aquatic toxicity on invertebrates, growth inhibition of algae. Therefore, these data will be available for the majority of substances. This data will enable qualitative judgments of the TK behaviour."
Several studies are available investigating the absorption, distribution, metabolism and excretion of oxalic acid and its salts, e.g.: dipotassium oxalate. Based on the available data (standard information for Annex VII registrations: 1-10 t/a) and the gathered information from publicly available studies the toxicokinetic behaviour of dipotassium oxalate will be predicted.
- Parameters analysed / observed: Absorption, distribution, metabolism and excretion

GLP compliance:

no

Radiolabelling:

yes

Remarks:

Most of the studies which were considered for compiling the statement used radiolabelled oxalic acid or oxalates. Please refer to the statement included in the endpoint summary under "Additional information"

Species:

other: rat, human

Strain:

other: Wistar, Sprague Dawley, Psammomys obesus Cretzschmar, Neotoma albigula Hartley, Osborne-Mendel white rats

Details on species / strain selection:

Mainly dependent on the age of the published results the strains used differ from the strains recommended by the current guidelines, however, this is not considered to have any impact on the outcome of the studies.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
The test animals were maintained according to the respective directives and recommendations that were actual in the year of conduction.

Route of administration:

other: via diet, intravenously, oral gavage

Vehicle:

other: mainly water or isotonic saline

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

preparations were made freshly before the experiments except for diets which were prepared once at the start of the experiments

Duration and frequency of treatment / exposure:

3h, 4h, 24h, 48 h dependent on the type of study

No. of animals per sex per dose / concentration:

n/a

Control animals:

not specified

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, expired air, blood, plasma, serum or other tissues, cage washes, bile

Type:

excretion

Results:

The major routes of excretion for substances from the systemic circulation are the urine and/or the feces. Excretion by exhalation does not seem to be relevant as demonstrated by Hodgkinson et al.(1978).

Type:

metabolism

Results:

The presented studies indicate that Oxalic acid and its salts are ubiquitously occurring molecules that are fast excreted and not further metabolised.

Type:

metabolism

Results:

Probably based on the bacterial oxalate degradation, similar observations were also reported for other mammals, e.g. rodents (Shirley and Schmidt-Nielsen, 1967).

Type:

metabolism

Results:

Once Oxalic acid is synthesised, it is excreted by urine or bile. Other organisms are capable of using oxalic acid as carbon source for energy supply (Abratt VR et al., 2010).

Type:

metabolism

Results:

Oxalic acid is known to be a degradation product of the intermediary metabolism. As mentioned before, it is generated during protein- or polypeptide metabolism, in carbohydrate metabolism and can also be found during the metabolism of ethylene glycol.

Type:

distribution

Results:

Sugimoto et al. (1993) found also that labelled Oxalic acid when administered intravenously was primarily renally excreted and to a small amount also by bile.

Type:

distribution

Results:

When administered by throat probe to rats Oxalic acid rapidly accumulated in the kidney and in the intestine, further substantiating that Oxalic acid is mainly excreted unchanged via urine and to a smaller extent binds to bile and is excreted by feces.

Type:

distribution

Results:

As a small molecule a wide distribution can be expected. The main occurrence of Oxalic acid was detected in the urine (89 to 99% recovery; Elder and Wyngaarden, 1960) when labelled Oxalic acid was intravenously administered to man.

Type:

absorption

Results:

If taken up by inhalation, It will possibly immediately be renally excreted and therefore be indistinguishable from oxalic acid taken up from other sources.

Type:

absorption

Results:

With its very low vapour pressure and a median particle diameter of 397.8µm dipotassium oxalate is not considered to be inhaled.

Type:

absorption

Results:

In feces about 10% of the radioactivity was detected and about 4 to 5 % of it is recovered in the body tissues (Hodgkinson, 1978). Studies evaluating the oxalate distribution and excretion in man revealed a total recovery of oxalate in urine of 90-100%.

Type:

absorption

Results:

It was reported that up to 60% of intravenously administered and labelled Oxalic acid is renally excreted in the rat within 24 h and about 1% are renally excreted within 48 h. In feces about 10% of the radioactivity was detected.

Conclusions:

Based on the available information dipotassium oxalate is readily orally absorbed, is excreted mainly by urine and to some extent in feces and is generally not metabolised but rather excreted unchanged.

Description of key information

expert statement based on physico-chemical properties and several publicly available studies

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic expert statement dipotassium oxalate

Data from in vitro or in vivo studies, which were designed to identify the toxicokinetic properties of Dipotassium oxalate are not available. But there are published results substantiating the assumed toxicokinetic behaviour which is in line with the physico-chemical properties of Dipotassium oxalate.

 

Parameter	Value used for CSR
Molecular Weight	166.22 g/mol
Melting Point	138°C decomposition
Boiling Point	n.a. (decomposition)
Density	2.2 g/cm^3
Vapour Pressure	< 1.0 E-007 hPa
Partition coefficient n-octanol/water (log Kow)	< -5.2
Water solubility	392 g/L
pKa 1	1.23 (Oxalic acid)
pKa2	4.19 (Oxalic acid)
Particle size	D50: 397.8 µm

 

Oral absorption

Dipotassium oxalate has a molecular weight of less than 500 g/mol and a log Kow of <-5.2 which is in general a prerequisite for absorption. Due to its structure dipotassium oxalate possesses two pKa values therefore, it will be present in its unionized form in stomach (pH 2) as well as in the small intestine (pH 8) which is also favourable for absorption. Dipotassium oxalate exhibits a good water solubility (392 g/L) and based on the ionic structure the substance is expected to dissociate in aqueous solutions thereby forming potassium ions and free oxalic acid. Oxalic acid is a ubiquitous occurring molecule which occurs during degradation of proteins and polypeptides or carbohydrates. Furthermore, oxalic acid can be found in many plants such as spinach or rhubarb. Hence, most animals are exposed to endogenously produced or exogenously oxalic acid. However, it is generally accepted that in the more alkaline medium of the intestine free oxalate is more likely to bind calcium or other ions thereby forming insoluble salts which are the primary cause of kidney stones and thus are the chemical species that exhibits toxicity. It was reported that up to 60% of intravenously administered and labelled Oxalic acid is renally excreted in the rat within 24 h and about 1% are renally excreted within 48 h. In feces about 10% of the radioactivity was detected and about 4 to 5 % of it is recovered in the body tissues (Hodgkinson, 1978). In contrast, studies evaluating the oxalate distribution and excretion in man revealed a total recovery of radiolabelled oxalate in urine of 90-100% and none was measured in exhaled CO₂. Based on these results the absorption of oxalic acid is assumed to be nearly 100%, for this reason it can be considered that the absorption rate for Dipotassium oxalate is 50 % for both animals and humans with respect to ECHA endpoint specific guidance Chapter 7c.

 

Respiratory absorption

Dipotassium oxalate is a solid at room temperature and decomposes at >138°C together with a low vapor pressure of < 1.0 E-007 hPa substance evaporation and uptake by inhalation is unlikely. However, the uptake after direct inhalation of substance dust particles and aerosols is possible because Dipotassium oxalate is marketed and used in a granular form, but considered very unlikely because the median particle size was determined to be D50 = 397.8 µm which is above the critical size for particles to be inhaled (i.e. 100 µm). Nevertheless, after uptake Dipotassium oxalate it will be readily absorbed due to its physicochemical properties, i.e. its water solubility (392 g/L) or its low log Kow (<-5.2) and is therefore unlikely to be coughed or sneezed out of the body. It will be taken up and possibly immediately be renally excreted and therefore be indistinguishable from oxalic acid taken up from other sources (i.e. diet). A deposition into lymphoid tissues is also rather unlikely.

Because Dipotassium oxalate is produced and marketed in granular form accidental exposure to dusts cannot be excluded. Thus, for precautionary reasons the estimated absorption of Dipotassium oxalate via the respiratory tract is 100%.

 

 

Dermal absorption

According to ECHA endpoint specific guidance Chapter 7c a substance “must first penetrate into the stratum corneum (non-viable layer of corneocytes forming a complex lipid membrane) and may subsequently reach the viable epidermis, the dermis and the vascular network” in order to enter the body via the dermis. Due to its low molecular weight (166.2 g/mol), its low log Kow (<-5.2) and its high water solubility (392 g/L), Dipotassium oxalate is rather unlikely to be dermally absorbed. A dermal absorption can be considered if the substance has a molecular weight of less than 500 and its LogKow is between -1 and 4. In other cases such as in the case of Dipotassium oxalate a reduced absorption of 10% is chosen (de Heer et al., 1999). If water solubility is above 10,000 mg/Land the log P value

below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. dermal uptake for these substances will be low. For substances with log P values <0, poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Values <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low. Furthermore, it was shown (Annex VII Dossier information for CAS 583-52-8), that Dipotassium oxalate is not a skin irritant nor a skin sensitizer, properties which would in both cases enhance or substantiate dermal penetration, respectively.

Based on the pKa values of oxalic acid of which one is 1.23 and the other is 4.19 Oxalic acid is supposed to be partially ionized, but due to its small size (MW 166.22 g/mol) it is presumably absorbed. However, since Dipotassium oxalate is handled in its solid form, it is not expected to be dermally absorbed. Thus, because uptake of Dipotassium oxalate by dermal route is not expected but can also not be excluded and because dermal absorption is not expected to exceed oral uptake a value of 10% absorption after dermal exposure should be assumed. However, lower values for dermal absorption cannot be considered due to lack of data.

 

Distribution

Dipotassium oxalate is assumed to dissociate either shortly before absorption in the GI-tract or thereafter, thus, the distribution of the free acid is considered. As a small molecule a wide distribution can be expected. However, it was reported that the main occurrence of Oxalic acid was detected in the urine (89 to 99% recovery; Elder and Wyngaarden, 1960) when labelled Oxalic acid was intravenously administered to man. None of the amount of administered Oxalic acid was detected in the exhaled CO₂. When administered by throat probe to rats Oxalic acid rapidly accumulated in the kidney and in the intestine, further substantiating that Oxalic acid is mainly excreted unchanged via urine and to a smaller extent binds to bile and is excreted by feces (Hagmaier et al., 1980). Sugimoto et al. (1993) found also that labelled Oxalic acid when administered intravenously was primarily renally excreted and to a small amount also by bile. Other studies suggested that labelled Oxalic acid can be also found in bones probably due to the high amount of calcium in bones and an enhanced affinity for Oxalic acid to bind calcium. No information on other potential target organs is available. However, as demonstrated by the studies mentioned above, Oxalic acid is mainly excreted via urine.

 

Metabolism

As a ubiquitous occurring molecule, Oxalic acid is known to be a degradation product of the intermediary metabolism. As mentioned before, it is generated during protein- or polypeptide metabolism, in carbohydrate metabolism and can also be found during the metabolism of ethylene glycol. Once Oxalic acid is synthesised, it is excreted by urine or bile. Other organisms are capable of using oxalic acid as carbon source for energy supply (Abratt VR et al., 2010). Probably based on the bacterial oxalate degradation, similar observations were also reported for other mammals, e.g. rodents (Shirley and Schmidt-Nielsen, 1967). In this study some of the administered labelled oxalate was found to be recovered in CO₂. The presented studies indicate that Oxalic acid and its salts are ubiquitously occurring molecules that are fast excreted and not further metabolised. Furthermore, the fast excretion seems to be dependent on the presence of higher concentrations of Oxalic acid in the gut and also on the amount of endogenously produced oxalates.

 

Elimination

The major routes of excretion for substances from the systemic circulation are the urine and/or the feces. Excretion by exhalation does not seem to be relevant as demonstrated by Hodgkinson et al.(1978).

As depicted above, Dipotassium oxalate is expected to dissociate into oxalic acid and potassium ions either before or after intestinal uptake. The orally administered amount of dipotassium oxalate will be fast excreted via urine and bile and is not further processed in the intermediary metabolism. However, free oxalate may bind other ions like calcium thereby forming almost insoluble oxalate salts which are known to be the cause of renal stones.

 

Bioaccumulation

Based on the log Kow of < -5.2 the substance is unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace.

References

Abratt, Valerie R., and Sharon J. Reid. "Oxalate-degrading bacteria of the human gut as probiotics in the management of kidney stone disease." Advances in applied microbiology. Vol. 72. Academic Press, 2010. 63-87.

 

Shirley, Emily K., and Knut Schmidt-Nielsen. "Oxalate metabolism in the pack rat, sand rat, hamster, and white rat." The Journal of Nutrition 91.4 (1967): 496-502.

 

Hagmaier, V., et al. "Anatomical Distribution of Exogenous 14C-Oxalate in the Rat by Macroautoradiography." European Urology 6 (1980): 172-174.

Sugimoto, T., et al. "Fate of circulating oxalate in rats." European urology 23 (1993): 485-489.

Bannwart, C., et al. "Absorption of oxalic acid in rats by means of a 14C method." European Urology 5 (1979): 276-277.

Hodgkinson, A., and R. Wilkinson. "Plasma oxalate concentration and renal excretion of oxalate in man." Clinical science and molecular medicine 46.1 (1974): 61-73.

Elder, T. David, and James B. Wyngaarden. "The biosynthesis and turnover of oxalate in normal and hyperoxaluric subjects." The Journal of clinical investigation 39.8 (1960): 1337-1344.