Formic acid

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Formic acid may be absorbed via the oral, dermal, and inhalation routes of exposure. Local toxicity may be seen due to its corrosivity. Systemically, formic acid will be present as the formate anion at physiological pH-values. Formate is metabolised by hepatic folate-dependent reactions and does not accumulate. Formate blood levels are generally low . Levels may be high during poisoning, e.g. with formate salts or methanol, because the limited human formate metabolism capacity may be exceeded. Systemic toxicity (acidosis and related metabolic disorders;  photoreceptor damage) may then occur.
Short description of key information on absorption rate: 
Dermal absorption of formic acid is known to occur from several cases of incidental poisoning.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

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. In a first step, it should be mentioned that the formate anion is the common metabolite of formic acid and formate salts in aqueous solutions at physiological pH values. This allows a read across results between different forms of formates.

Discussion on bioaccumulation potential result:

The water soluble formic acid and formate salts rapidly dissociate in aqueous solutions (water, body fluids) to formate and the cation ( H⁺or Na⁺,K⁺,NH₄⁺, etc.).  The pKa for 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 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.

 

Formate is the common metabolite of formic acid and formate salts.  Formate is formed from precursors in the intermediary metabolism and 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 also be formed from ingested methanol via formaldehyde and further oxidation to formate.

Pharmacokinetic models have been established from methanol inhalation studies 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.  The 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 minutes) < cat (67 minutes) < dog (77 minutes) < pig (87 minutes).  This reflects the species differences in the hepatic concentrations of folates and folate-dependent enzymes which affect the formate degradation to CO₂.  Only minor quantities are excreted unchanged via urine in all species. 

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. Photoreceptor toxicity and damage to the eye may occur in humans under such conditions.

 

Formic acid and formate salts may be absorbed via the oral route.  Formic acid may generate vapours that can be taken up by inhalation.  Dermal uptake may also occur with formic acid.

Target organs for formic acid are as follows:

Local toxicity due to corrosivity: skin and eye after direct contact; upper inhalation tract after inhalation; mouth, larynx, pharynx, esophagus, stomach, intestines after orall ingestion.

Systemic toxicity: none.

Discussion on absorption rate:

Dermal absorption of formic acid is known to occur. Systemic toxicity, acidosis, and elevated formate blood levels were described in clinical case reports following incidental poisoning. For further details see the publications described in sections "direct observations: clinical cases, poisoning incidents and other" (Chan, 1995; Malizia, 1977; Sigurdsson, 1983).

The exposure conditions of these cases had in common that large areas of the skin were affected, and that the formic acid was highly concentrated.