Potassium formate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Formate anion is the common metaboliteof formate salts in aqueous solution, which allows cross reading between different substances. Formates are rapidly absorbed after oral ingestion and distributed as a result of the high water solubility. Metabolism to carbon dioxide occurs almost exclusively in the liver and depends on folates. Urinary formate excretion is of minor importance. Human hepatic folate levels are only 50% of that in rodents. The plasma elimination rate is therefore higher in rodents. The elimination follows first order kinetics in all species and there is no bioaccumulation potential. However, under certain conditions (e.g. methanol poisoning; ingestion of large quantities of formate) leading to very high plasma levels persisting over longer time periods, lesions of photoreceptor cells may occur in humans.
Short description of key information on absorption rate: 
In the absence of valid studies, a dermal absorption of 1% is assumed for formate salts and used in exposure assessments. This estimate is considered to be conservative because ionised substances do not penetrate very much.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

1

Additional information

The toxicokinetic behavior, metabolism and elimination of formic acid, formate salts and methanol as a formic acid precursor was extensively studied in several species including humans, and there are significant species differences which need to taken in to account. Most notably is that the formate anion is the common metabolite of formic acid and formate salts in aqueous solutions at physiological pH values. This allows cross reading of results between different forms of formates. Differences between the two alkali metal ions, sodium and potassium, are considered to be negligible in this context.

Potassium formate is expected to behave similar to sodium formate, which is rapidly absorbed after oral ingestion and distributed due to its water solubility. Formate metabolism (first order oxidation to carbon dioxide) occurs almost exclusively in the liver. Urinary excretion is of minor importance. The metabolic rate is generally high in mammals, but there are species specific differences resulting from the differences in the hepatic folate concentrations. Levels in primates are approx. 50% of those in rodents. Formate accumulation is unlikely to occur, but temporarily elevated levels may occur under certain conditions which largely exceed the metabolic capacity (poisoning with methanol or large amounts of formate salt).In such instances eye lesions may occur in humans.

Discussion on bioaccumulation potential result:

Formic acid and formate salts are water soluble and dissociate rapidly in aqueous solutions (water, body fluids) to formate and the cation ( H⁺or Na⁺,K⁺,NH₄⁺, etc.).  The pKa of formic acid is 3.70 at 20 °C, and the equilibrium in equation [1a] is therefore far on the right side at physiological pH. 

 

               HCOOH              < --- >          HCOO^-+ H⁺                  [1a]

HCOOK               < ---- >           HCOO^-+ K⁺                  [1b]

 

Calculations of the chemical behavior of potassium diformate and formic acid solutions from titer curves indicate that the equilibrium in equation [2] is in favor of potassium diformate at pH < 4 and at concentration below 0.1 % (Hydro Research Centre, 1997).

  

    HCOOH-HOOCK       < ---- >           HCOOH + HCOOK            [2]

 

At pH values of 4 to 5, and at dilution down to 0.001%, most of the formic acid content is released from potassium formate. Upon further dilution and increase of pH above 5 the concentrations of formic acid and diformate decrease rapidly, leaving only formate at pH 7 and above. No formic acid or diformate exists above pH 7 (Hydro Research Centre, 1997). Formate is therefore the common metabolite of formic acid and formate salts, which allows to read across results from either test substance provided that the respective formula weights are taken into account (OECD SIDS Formic acid and formates category, 2008; cf. section 13).

 

Formate salts are solids that may be absorbed via the oral route, whereas dermal absorption is considered to be low (EU guidance document. Anonymous, 2004). Inhalation of formate dust may occur to some extent predominately in industrial settings.Formate is also formed from precursors in the intermediary metabolism, and it is used as an important constituent of the C1 intermediary metabolism which is required for the biosynthesis of amino acids and nucleic acid bases (purines and pyrimidines). Formate may further be formed from ingested methanol via formaldehyde and further oxidation to format(OECD SIDS, 2008; cf. section 13).

Pharmacokinetic models have been established, from methanol inhalation studies and from ex vivo experiments using the isolated perfused rat liver, which allow calculating the time course of all metabolites including formate in good correlation with animal studies.  Peak plasma formate levels were reached within 1 hour (rabbits) and 4-5 hours (pigs) after oral administration of potassium diformate, and within 10 to 30 minutes in humans who ingested up to 4.4 g sodium formate or 2.0 g formic acid.  The formate elimination from blood follows first order kinetics and the blood levels rapidly return to background levels in all species, i.e. formate does not persist or accumulate.  However, there are significant species differences in the elimination rates and the elimination half-lives (from plasma):  rat (12 minutes) < guinea pig (22 minutes) < rabbit (32 minutes) < humans (45 to 60 minutes) < cat (67 minutes) < dog (77 minutes) < pig (87 minutes) (Malorny, 1969; Hanzlik et al, 2005; OECD SIDS, 2008; cf. section 13). The formate oxidation to carbon dioxide occurs predominantly in the liver, as evidenced in the isolated perfused rat liver, or in rabbits where the inhibition of folate enzymes increased the elimination half-live from 32 minutes in untreated animals to 130 minutes (Cook et al., 2001; Eells et al., 2000 insection 7.9.3). In all species, only minor quantities are excreted unchanged via urine. The variation of the elimination rate reflects the species differences in the hepatic concentrations of folates and folate-dependent enzymes which affect the formate degradation to CO₂(Malorny, 1969; Black et al, 1985; Johlin et al., 1987; Eells et al., 2000; Martin-Amat, 1978).

High formate plasma levels may occur in humans under special conditions, i.e. if the formate elimination capacity is exceeded, for example after ingestion of large amounts of formate salts or during methanol poisoning. Photoreceptor toxicity and damage to the eye may occur in humans under such conditions. See section 7.9.3 for further details.

 

Target organ characteristics for potassium formate:

Local skin and eye reactions were not seen.

Systemic toxicity: no other expected than photoreceptor cells and optical nerve after high doses.

Discussion on absorption rate:

Dermal absorption is considered to be low, but no study is known to exist. A conservative approach proposed by the European Commission (Guidance Document on Dermal Absorption, 2004) is to assume a dermal absorption rate of 10% is in case the molecular weight is >500 and the log Pow is smaller than -1 or higher than 4, and otherwise to assume 100% absorption. The Guidance is available under http://ec.europa.eu/food/plant/protection/evaluation/guidance/wrkdoc20_rev_en.pdf

In the case of formate salts the dermal absorption is considered to be 1% because the salt is highly water soluble, and fully ionized in aqueous solution. It is known, and also stated in the Guidance Document, that highly ionized substances do not penetrate very much. As a first approach, a dermal absorption of 1% is assumed and used in exposure assessments.