Sodium formate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Objective of study:

other: rate of formic acid dissociation at physiological pH

Principles of method if other than guideline:

Calculation of the chemical behavior of potassium diformate and formic acid solutions from titer curves.

GLP compliance:

no

Radiolabelling:

no

Species:

other: calculation

Potassium formate is expected to form the following equilibriums in  aqueous solutions: 

1)   HCOOH-HCOOK         <-->         HCOOH  +  HCOOK  [equation 1]

2)         HCOOH                <-->              HCOO-  +  H+     [equation 2] 

3)         HCOOK          <-->         HCOO-  +  K+     [equation 3]     

Mapping the pH as function of dilution and titer curve allowed to estimate the buffer effect of the diformate system (equation 1) 

and to  calculate the concentration profile of diformate, formic acid and formate  as function of concentration in water solutions. 

The calculations indicate that in aqueous solutions

i) at pH <4 and at concentrations >0.1% the equilibrium in equation 1 is  in favor of potassium diformate.

ii) at pH of 4 to 5, and at dilution down to 0.001%, most of the formic acid content is released from potassium formate.

iii) further dilution and increase of pH above 5, the concentrations of  formic acid and diformate decrease rapidly, leaving only formate left at 

pH 7 and above. No diformate exists above pH 7.

Conclusions:

Interpretation of results (migrated information): other: potassium diformate, formate, and formic acid are in equilibrium in aqueous solution. At physiological pH values around 7, the equilibrium is in favor of formate.
Read across can be made between formic acid and formate salts provided that the pH value of aqueous solutions is around neutral.

Executive summary:

Formic acid is in equilibrium with its salts in aqueous solutions. No diformate or formic acid exists above pH 7, only formate is left. The pKa for the dissociation of potassium diformate into formic acid and potassium formate (equation 1) is approx. 4.3. The pKa for formic acid is approx. 3.75 (equation 2). Formate salts dissociate in aqueous solution (equation 3).

1)   HCOOH-HCOOK        <-->         HCOOH  +  HCOOK  [equation 1]

2)         HCOOH                 <-->             HCOO-  +  H+     [equation 2] 

3)         HCOOK         <-->         HCOO-  +  K+     [equation 3]     

The equilibrium is in favor of formate at neutral pH values. Therefore, read across can be made between formic acid and formate salts provided that the pH value of aqueous solutions is around neutral (Hydro Research Centre, 1997).

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Toxicokinetic modeling: in vivo - in vitro correlations using the perfused rat liver. Development of a toxicokinetic model using data from perfused rat liver experiments, and model evaluation in vivo.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): sodium formate

Radiolabelling:

no

Species:

rat

Route of administration:

other: C34-001:perfusate (perfused liver experiments) and i.v. (in-vivo experiments)

Vehicle:

water

Dose / conc.:

2 other: mM

Remarks:

in vitro test; in terms of sodium formate

Dose / conc.:

4 other: mM

Remarks:

in vitro test; in terms of sodium formate

Dose / conc.:

8 other: mM

Remarks:

in vitro test; in terms of sodium formate

Dose / conc.:

12 other: mM

Remarks:

in vitro test; in terms of sodium formate

Dose / conc.:

41 mg/kg bw (total dose)

Remarks:

in vivo test; in terms of sodium formate

Dose / conc.:

164 mg/kg bw (total dose)

Remarks:

in vivo test; in terms of sodium formate

Dose / conc.:

328 mg/kg bw (total dose)

Remarks:

in vivo test; in terms of sodium formate

Dose / conc.:

492 mg/kg bw (total dose)

Remarks:

in vivo test; in terms of sodium formate

No. of animals per sex per dose / concentration:

Males: 92

Control animals:

yes

Details on study design:

- Dose selection rationale: dose levels were estimated from target plasma concentration assuming a rapid mixing after intravenous injection and a total body water volume of 60% of the body weight.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (in vivo)
- Tissues and body fluids sampled: urine, blood
- Time and frequency of sampling:
Blood: at 15 min before dosing and 5, 10, 15, 20, 30, 40, 50 min and 1, 1.25, 1.5, 1.75., 2, 2.25, 2.5, 2.75, and 3 hr after dosing.
Urine: 20 min and 3, 8, 12, 20, and 28 hr after dosing.

Details on absorption:

not applicable (i.v. injection)

Details on distribution in tissues:

not examined

Details on excretion:

Urinary excretion at 3 hours after dosing accounted for 8/34/45/55% at plasma target levels of 1/4/8/12 mM.

1) Perfused liver
i) experiment without liver: formate was not lost from the perfusion system without liver.
ii) experiments with liver: elimination of formate was dose-dependent. Saturation of metabolic elimination was

evident beginning at 4 mM. Formate elimination was virtually linear when plotted on a linear scale. Elimination rates calculated from the slope of the elimination curves for the 2, 4, 8, and 12 mmM dose were 7.1, 16.0, 22.8, and 26.4 µmol/hour/g liver, respectively. Good agreement between the model prediction and the measured perfusate concentrations were obtained (correlation coefficient r²= 0.9996). 

Table 1: statistical results for the perfused liver model:  

Maximal rate	Vmax  = 0.0100 mmol/min
Michaelis constant	KM    = 1.324 mM
endogenous liver formate production	KO    = 0.002 mmol/min

2) In-vivo studies

Elimination of formate from plasma was very rapid at all dose levels. Endogenous levels (approx. 0.06 mM) were

reached at approx. 3 hours.  The plasma curves showed nonlinearities in the elimination of formate across doses in

the log concentration-time plot.

Urinary excretion was initially very rapid. The cumulative excretion had reached the steady state condition of the endogenous formate excretion 

3 h after dosing.

Table 2: Urinary formate excretion in the rat
 

Target concentration  (mM)	Dose (mg/kg bw)	Total dose (mmol)	Urinary excretion (% of dose by 3 hours)
			Experiment (mean, n=4)	Model prediction
1	41	0.21	19	8
4	164	0.84	35.1	34
8	328	1.68	42.7	45
12	492	2.52	48.3	55

3) The toxicokinetic model 
The toxicokinetic model predicted both the rapid initial excretion and the steady state concentrations in good

agreement with the in-vivo  experiments, indicating a good fit of the model. Predictions for the in-vivo experiments (tabulated below) were in good agreement with the perfusion data.

Table 3: Model predictions for the in vivo situation

Maximal rate	Vmax  = 0.016 mmol/min
Michaelis constant	KM    = 1.84 mM
endogenous liver formate production	KO    = 0.00052 mmol/min

 

The simulated proportions of formate excretion via hepatic metabolism and urinary excretion indicate that the liver can account for virtually all formate metabolism in vivo:
 

Dose level (mM)	% of dose elimiminated by 3 hours)
	Hepatic metabolism	Urinary excretion
1	92	8
4	66	34
8	55	45
12	45	55

 

Regarding the toxicological behavior: Elimination follows Michaelis-Menten kinetics. Hepatic metabolism  prevails at plasma levels up to 1 mM. Urinary elimination

 accounts for up  to 50% at high plasma levels. No accumulation to be considereed in the rat in-vivo.

Conclusions:

Data obtained in rat perfused liver experiments indicated that formate is rapidly eliminated from the perfusate at all tested perfusate concentrations of 2, 4, 8, and 12 mM. The elimination was dose dependent, and metabolic saturation was seen at 4 mM and above.
A 2-compartment toxicokinetic model was developed and used to predict the elimination of formate. The model prediction fitted well with the
measured values and allowed to calculate the Michaelis-Menten constants of the metabolic reactions.
In-vivo experiments confirmed both the model prediction and the results of the liver perfusions.
Key findings of the presented studies include:
i) The rat perfused liver model and the toxicokinetic model were both suitable to model the in-vivo situation following low and high formate doses.
ii) Elimination of formate in vivo is saturable and follows Michaelis-Menten kinetics. Predicted constants are Vmax=0.016 mmol/min and
KM=1.84 mM.
iii) The endogenous formate generation in liver is calculated to be KO=0.00052 mmol/min.
iv) Hepatic metabolism of formate prevails (92% of elimination) over urinary excretion (8%) at the low dose (1 mM). At physiological plasma levels
(approx. 0.06 mM) hepatic metabolism is considered to play the major role for elimination. At higher plasma levels the urinary excretion
accounted for op to approx. 50% of the elimination.
v) In the in-vivo experiments, plasma levels of up to 12 mM returned to normal (0.06 mM) within 3 hours after dosing.
Thus, there was no indication of accumulation of formate in the rat.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Examination of plasma levels, blood pH, and urinary excretion following ingestion of sodium formate or formic acid.

GLP compliance:

no

Specific details on test material used for the study:

- Test substance: formic acid and sodium formate

Radiolabelling:

no

Species:

human

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

water

Dose / conc.:

1.48 other: g

Remarks:

in terms of sodium formate; equivalent to 1 g of formic acid

Dose / conc.:

2.96 other: g

Remarks:

in terms of sodium formate; equivalent to 2 g of formic acid

Dose / conc.:

4.44 other: g

Remarks:

in terms of sodium formate; equivalent to 3 g of formic acid

Dose / conc.:

2 other: g

Remarks:

in terms of formic acid

No. of animals per sex per dose / concentration:

In total 16 volunteers

Toxicokinetic parameters:

half-life 1st: 45 min

1) Urinary excretion

i) Sodium formate
The urinary excretion (24-h urine) of formate under normal background  conditions was approx. 13 mg/24 h. Following the ingestion of 

sodium  formate, 2.1% of the dose was excreted in urine within 24 hours. At  higher doses there was a trend towards an increased excretion.

===========================================================
Dose       n     total FA       24-h urinary excretion 
(mg)               (mg)          (% of dose)
-----------------------------------------------------------
0, normal 12    13.04+/-1.68  (mean volume 917 mL, (report, table 1)

i.e. 14.2 mg/L)
  
Sodium formate       
1480      12                       2.10+/-0.35 (report,table 1)
 
1480      12                       2.24 (report, table 2)

2960       7                       3.30 (report, table 2)

2960       1                       4.72 (report, table 4)

4400       1                       7.03 (report, table 4)

Formic acid
2000       1                       3.81 (report, table 5)
       
===========================================================

Urinary excretion was rapid as 65 and 84% of the formic acid excreted appeared in urine within the first 6 hours after ingestion of 

1480 and  2960 mg, respectively. Control levels were reached in urine samples 12 h after doses of 1480 and 2969 mg sodium formate.

It was also noted that the urine volume and pH were both increased after  the ingestion of formate.

ii) Formic acid
3 experiments were conducted with formic acid, ingested as a 0.4% aqueous  solution. The total urinary excretion was 3.81% of the dose 

within 24 h (report, table 5).  It was thus comparable with the excretion observed after dosing formate.

2) Kinetic
i) Absorption
The plasma formate levels were examined following the ingestion of 2960 and 4400 mg sodium formate (equivalent to  2000 and 

3000 mg formic acid),  and after 1000 and 2000 mg formic acid. Formate and formic acid were both rapidly absorbed and reached peak levels 

within 10 to 30 minutes (report, table 3).

ii) Blood pH
The blood pH-value remained largely unchanged (report, table 3).

===========================================================
                  Dose
           -------------------
Time       NaHCOO        HCOOH     Plasma        pH
(min)                              formate
                                  (mg/100 ml) 
-----------------------------------------------------------
Blank       -              -         0.46       7.37

          ------------------------------------------        
 15                      1000        0.31       7.35
 30                        "         n.d.       7.37  
 45                        "         0.51       7.40         

60                        "         0.31       n.d.
 90                        "         0.31       7.39
          ------------------------------------------ 
 15                      2000        1.24       7.37
 30         2960     (equiv. 2000)   4.32       7.35         

30                      2000        1.70       7.32  
 45                      2000        2.01       7.34
 60          "                       1.86       7.39  
 60                      2000        2.01       7.35
 90                      2000        1.70       7.35
120          "                       0.93       7.35
240          "                       0.93       7.33    
          ----------------------------------------- 
 10         4400     (equiv. 3000)  11.80       7.33         

20                                 12.05       7.33  
 40                                  9.58       7.34
 60          "                       8.18       7.33  
 90                                  4.78       7.33
120          "                       3.55       7.32
===========================================================

ii) Elimination from plasma
Plasma levels were examined in 2 individuals receiving 2960 or 4400 mg sodium  formate, respectively. The plasma half-life times (t1/2) were 

calculated  to be 45 min (report, Fig 1)and 46 min (report Fig. 2), respectively .

ii) Elimination from plasma
Plasma levels were examined in 2 individuals 2960 or 4400 mg sodium formate, respectively. The plasma half-life times
(t1/2) were calculated to be 45 and 46 min, respectively.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
In human volunteers formic acid and sodium formate were rapidly absorbed with maximum plasma levels at 10 to 30 minutes after ingestion. Resorption of the protonated form starts already in the stomach. Elimination from plasma was rapid with a half-life time of approx. 45 minutes. Urinary excretion was low . Formic acid and formate anion behave very similar; the latter is protonated in the stomach.

Executive summary:

The toxicokinetic behavior sodium formate and formic acid was examined in a total of 16 human volunteers who ingested up to 4.44 g of sodium formate or up to 2 g formic acid in a pre-guideline study.

Formate and formic acid are both rapidly absorbed and reach peak plasma levels within 10 to 30 min after ingestion. Resorption of the unprotonated acid begins already in the stomach. Sodium formate is converted to the unprotonated acid under the pH conditions of the stomach. Formate is eliminated from the plasma with a half-life time of t_1/2= 45 min. Urinary excretion is rapid within the first 6 hours after ingestion and returns to normal levels at 12 hours after dosing. Urinary excretion is generally low, it accounts for approx. 2.1 - 3.3% of the administered dose. The blood pH remains unchanged following single formate or formic acid doses that are equivalent to 3000 mg formic acid. Urine volume and pH were increased as long as formate was excreted via urine (Malorny, 1969).

 

This pre-guideline study is considered to be valid and provide information for assessment.

 

 

Reference 4

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

; absorption and excretion in human subjects following a single oral fixed dose

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): calcium formate
- Substance type: salt
- Physical state: solid
- Other:
Calcium formate (650 mg/capsule) and placebo capsules were custom formulated by Opti-Med inc., Seymour, IN, USA)

Radiolabelling:

no

Species:

human

Strain:

other: not applicable

Sex:

female

Details on test animals or test system and environmental conditions:

Human subjects attending the study:
- Status: normal, healthy adults
- Sex: female
- Number: 14
- Age: between 19 and 33 years of age
- Body weight: mean 64.5 +/-11.2 kg.; range 51-93 kg
- Pregnant or breastfeeding: none

- Fasting: 10 hours overnight
- Drinking: subjects were allowed water ad libitum during the 4.5 hours after dosing

Route of administration:

oral: capsule

Vehicle:

water

Details on exposure:

Dosing:
- Subjects ingested either placebo or calcium formate
- Doses: 0 (placebo) or 3900 mg CaFo (6 capsules, 350 mg each)
- Vehicle: 240 mL water was ingested along with the capsules

Duration and frequency of treatment / exposure:

single oral dose

Dose / conc.:

3 900 other: mg

Remarks:

Mean dose: 60 mg CaFo/kg bw

No. of animals per sex per dose / concentration:

14

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: based on previous studies by Malorny (1969) and a preliminary study with 6 adult male volunteers (total 4550 mg/person)

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: time 0, and at 30, 60, 90, 135, 180, 225, and 270 min after dosing

Statistics:

Pharmacokinetic analyses were performed using Excel X. Elimination rate constants (kel) were calculated as minus the slope of a plot of lnC versus time, and half-lives (t1/2) from the relationship t1/2 = ln2/kel. AUC values were calculated by trapezual integration. Oral clearance and apparent volumes of distribution were calculated as (CL/F=dose/delta AUC) and (Vß/F=(CL/F) / kel, respectively, where delta AUC refers to the increment in formate AUC above the baseline area. Results are reported as mean +/- SD (report, table 1).

Details on absorption:

Calcium formate was rapidly absorbed. Maximal formate plasma levels (mean: 0.50 +/- 0.04 mmolar) were seen at 60 min after dosing.

Details on distribution in tissues:

No other tissue examined. The mean apparent distribution volume of 2.36 L/kg body weight indicates that the distribution in tissues follows the water solubility.

Details on excretion:

A monoexponential decline of serum concentrations with an average half-life of 59+/-7 minutes was seen to occur after 60 minutes post dosing. Baseline levels were reached by 225 minutes post dosing. The AUC was 49.4 +/- 6.2 mM x min, of this, 8.7+/-2.0 mM x min were attributable to endogenous formate. Thus, the net AUC resulting from 3900 mg of calcium formate was 41.2 +/-5.8 mM x min. From this and the formate dose given (60 mmol/subject) the oral clearance was (CL/F=1.95 L/min), and from this and the apparent elimination rate constant, the distribution volume was 156+/-27 liters, or 2.36+/-0.38 L/kg body weight.

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 59 +/- 7 minutes

Test no.:

#1

Toxicokinetic parameters:

Cmax: 0.50 +/- 0.04 mM

Test no.:

#1

Toxicokinetic parameters:

Tmax: 60 minutes

Test no.:

#1

Toxicokinetic parameters:

AUC: 41.2 +/-5.8 mM x min (net)

Test no.:

#1

Toxicokinetic parameters:

AUC: 8.7+/-2.0 mM x min (endogenous formate)

Test no.:

#1

Toxicokinetic parameters:

other: distribution volume: 2.36+/-0.38 L/kg body weight

Metabolites identified:

no

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Calcium formate was rapidly absorbed, metabolised and eliminated in female human subjects ingesting 3900 mg calicum formate.

Executive summary:

Blood samples were withdrawn from 14 healthy female adult subjects (19 to 33 years of age; mean body weight 64.5 kg) following ingestion of placebo and a total of 3900 mg calcium formate at 0, and at 30, 60, 90, 135, 180, 225, and 270 min after dosing. Serum formate concentration was measured using a fluorometric assay.  

The maximal serum levels (mean: 0.50 mM) was seen at 60 minutes after dosing, and a monoexponential decline of serum concentrations with an average half-life of 59+/-7 minutes thereafter. Baseline levels (placebo) were reached by 225 minutes post dosing. The AUC was 49.4 +/- 6.2 mM x min, of this, 8.7+/-2.0 mM x min were attributable to endogenous formate. Thus, the net AUC resulting from 3900 mg of calcium formate was 41.2 +/-5.8 mM x minute. From this and the formate dose given (60 mmol/subject) the oral clearance was (CL/F = 1.95 L/min), and from this and the apparent elimination rate constant, the distribution volume was 156+/-27 liters, or 2.36+/-0.38 L/kg body weight.  

The results indicate that calcium formate was rapidly absorbed,metabolised and eliminated after oral ingestion by female human subjects, and that formate does not have an accumulation potential (Hanzlik; 2005)  

The study was conducted similar to provisions of the OECD guideline No. 417, and is considered to be valid for assessment.

Reference 5

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Objective of study:

metabolism

Specific details on test material used for the study:

Sodium formate

Species:

mouse

Strain:

B6C3F1

Details on test animals or test system and environmental conditions:

TEST ANIMALS
-Strain: normal CB6-F1 mice and NEUT2 (hetero- and homozygous; deficient in cytosolic 10-formyltetrahydrofolate dehydrogenase).
- Age at study initiation: 3 to 10 months
- Weight at study initiation:
- Fasting period before study:
- Housing: single
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum): Teklad Rodent Diet No. 8604
- Water (e.g. ad libitum):
- Acclimation period:


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Photoperiod (hrs dark / hrs light): 12 /12

Route of administration:

intraperitoneal

Dose / conc.:

5 mg/kg bw (total dose)

Dose / conc.:

100 mg/kg bw (total dose)

1) Low-dose formate treatment (2 µmol; 5 mg/kg bw)

Normal mice rapidly metabolized formate to CO2. Inhibition of catalase by 3-aminotriazole had little effect. Metabolism was approx. 50% slower in NEUT2 mice.

======================================================
Mouse      Dose         CO2 expired within 60 min 
         (mg/kg bw)   (% of administered dose; means)
------------------------------------------------------
normal      5                       52.6
NEUT2       5                       27.6

normal     5 + 3-AT                 48.8
NEUT2      5 + 3-AT                 26.9
======================================================
3-AT = 3-aminotriazol

The authors concluded that at the low dose formate is not metabolized by catalase, but via 10-formyltetrahydrofolate dehydrogenase (FDH), which was responsible for the rapid initial oxidation of formate, and that approx. half of the
formate dose was oxidized via the FDH-dependent route.

2) High dose formate treatment (44 µmol; 100 mg/kg bw) At the high dose there was no difference between normal mice
and NEUT2 mice with respect to the proportion metabolized to CO2 within the first 60 minutes. Pretreatment with the catalase inhibitor 3-aminotriazole reduced the initial rate of formate oxidation by 45 -50% in
both normal and NEUT2 mice. The authors concluded that catalase is involved in the oxidation of formate at high concentrations.

======================================================
Mouse      Dose         CO2 expired within 60 min 
         (mg/kg bw)   (% of administered dose; means)
------------------------------------------------------
normal     100                       65.5
NEUT2      100                       66.0
======================================================

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results

Executive summary:

The authors concluded that mice oxidize formate by at least 3 different routes:

(1) folate-dependent via FDH (10-formyltetrahydrofolate dehydrogenase) at low levels of formate. NEUT2 mice are defient in FDH oxidise formate at approximately half the of normal mice.

(2) peroxidation by catalase at high formate levels; and

(3) by an unknown route which appears to function at both low and high levels of formate.

Reference 6

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

metabolism

GLP compliance:

no

Specific details on test material used for the study:

- Test substance: sodium formate

Species:

monkey

Route of administration:

intravenous

Dose / conc.:

50 mg/kg bw (total dose)

Dose / conc.:

72 mg/kg bw (total dose)

Dose / conc.:

200 mg/kg bw (total dose)

Dose / conc.:

255 mg/kg bw (total dose)

Dose / conc.:

470 mg/kg bw (total dose)

Toxicokinetic parameters:

half-life 1st: 40 min

(1) Clay and coworkers (1975) examined the elimination of sodium formate  in pigtail monkeys and rats. 
The calculated elimination half-time in monkeys ranged between 31 min  (dose: 50 mg formate/kg bw) and 51 min (470 mg formate/ kg bw).
The respective values in the rat were 12 min (100 mg/kg bw) and 23 min  (670 mg/kg bw). (cf. report, pages 56-57)


(2) Kavet and Nauss (1990):
The metabolic rate of formate in non-human primates (pigtail macaque) was  reported to be 0.75 mmol/kg bw and hour, i.e. approx. 

34 mg formate/kg bw  and hour. (cf. report p. 38, middle of right column)

Tox. behaviour: elimination t1/2 in primates: 31-51 min; dose-dependent

Executive summary:

(1) The elimination half-time in primates (pigtail monkey) ranged between 31 to 51 min after doses of 50 and 470 mg formate/kg bw, respectively. These values are in good agreement with other values fro primates reported in the literature. A dose-dependency of the elimination half-time, that had been reported in the literature, was confirmed in the rat and in primates (Clay, 1975).

(2) The hourly metabolic rate at which a non-human primate (pigtail macaque) eliminates formate was reported to be 0.75 mmol/kg bw, i.e. approx. 34 mg formate/kg bw. For a 65-kg human adult that would be equivalent to 2,2 g formate per hour. Kavet and Nauss (1990). An accumultion of formate is not considered to occur as long as the metabolic rate is not saturated

Reference 7

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well documented and acceptable for assessment. Review article, summarising pre-guideline studies.

Objective of study:

excretion

Principles of method if other than guideline:

Examination of urinary formate excretion following oral sodium formate uptake

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Na-Formiat

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

- Weight at study initiation: 375 g

Route of administration:

oral: drinking water

Dose / conc.:

1 other: % in drinking water

Remarks:

Equivalent to 730 mg/kg bw/day based on weight of 375 g at study initiation and 27.4 mL/d (274 mg/d)

No. of animals per sex per dose / concentration:

Males: 6

Control animals:

not specified

Details on study design:

- Dose selection rationale: not specified

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: 24-h urine was collected from animals receiving sodium formate for 1.5 years.
- Number of animals: 6

Statistics:

Calculation of means +/- standard deviation

Details on excretion:

Wistar rats receiving sodium formate as a 1% solution with the drinking water for 18 months excreted approx. 13.8% of the daily dose with the 24-hour urine. The urinary excretion was 3% in a second group of rats receiving an approx. 10-fold lower dose.

Metabolites identified:

yes

At the high dose level 13.8% of sodium formate were excreted as formic acid in the 24-h urine, compared to only 3% at approx. 10-fold lower doses.

Formate uptake and formic acid excretion (mean of 6 rats,
NaF 1% in drinking water).

=========================================================
A) Uptake    Volume        Uptake         equivalent
           Drinking water    NaF         Formic acid
            (ml/d)          (mg/d)          (mg/d)
---------------------------------------------------------
          27.4 +/- 4.5   274.0 +/- 44.5   185.4 +/- 30.3

=========================================================
B) Urinary     Volume     Excretion          % of dose
   Excretion   Urine     Formic acid         
               (ml/d)      (mg/d)               (%)
---------------------------------------------------------
          12.1 +/- 3.5   26.2.0 +/- 9.6      13.8 +/- 3.1

=========================================================

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Urinary formate excretion was low as a result of rapid metabolism in the rat.

Executive summary:

The urinary excretion of formate was examined in a chronic pre-guideline study. Wistar rats (n=6) receiving sodium formate as a 1% solution with the drinking water for 18 months excreted approx. 13.8% of the daily dose with the 24-hour urine. The urinary excretion was only 3% in a second group of rats receiving an approx. 10-fold lower dose (Malorny, 1969).

 

 

Reference 8

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

metabolism

GLP compliance:

not specified

Specific details on test material used for the study:

Formate: [14C]-labeled sodium formate and deuterated sodium formate.
Formaldehyde: [14C]-labeled formaldehyde and deuterated formaldehyde.

Radiolabelling:

yes

Species:

rat

Route of administration:

intraperitoneal

Dose / conc.:

0.67 other: mmol/kg bw

Remarks:

Males

Toxicokinetic parameters:

half-life 1st: 23.7 min

Toxicokinetic parameters:

half-life 2nd: 182 min

RS-Freetext:
The authors reported biphasic conversion of formate (and of
formaldehyde) to carbon dioxide. Half-life times were
approx. 24 min and 182 min when sodium formate was given by
i.p. injection. After dosing with sodium formate approx. 70%
of the dose was expired as carbon dioxide within 12 hours.

Similar results were obtained when the deuterated compounds
were given, i.e. there was no relevant isotope effect noted.

Reference 9

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Formate toxicokinetics and levels of enzymes and coenzymes involved in formate metabolism was examined in young swines

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): sodium formate
- Specific activity (if radiolabelling): 57 mCi/mmol
- Locations of the label (if radiolabelling): [14C] sodium formate

Radiolabelling:

yes

Species:

pig

Strain:

other: crossbred (Yorkshire x Duroc x Hampshire)

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: from the Department of Veterinary Clinical Sciences, Iowa State University
- Weight at study initiation: 9.5 to 14 kg
- Fasting period before study:
- Housing: individually in stainless steel cages
- Individual metabolism cages: no
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
no data

Route of administration:

intraperitoneal

Vehicle:

not specified

Details on exposure:

Animals were injected i.p. with [14C] sodium formate (500 mg/kg bw; 12,000 dpm/mg).

Duration and frequency of treatment / exposure:

Single dose

Dose / conc.:

500 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

6

Control animals:

no

Details on study design:

- Dose selection rationale: not specified

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, plasma, serum and liver samples
- Time and frequency of sampling: blood samples were collected by the ocular sinus technique at 90, 180, 240, and 300 min after dosing. A protein free supernatant was prepared by the use of zinc sulfate and sodium hydroxide.
- From how many animals: 6 pigs (samples not pooled)
- Method type for identification: Liquid scintillation counting

Statistics:

Student's t-test for unpaired data and linear regression were performed. P<0.05 was considered to be statistically significant.

Toxicokinetic parameters:

half-life 1st: 87 +/- 18 min in the pig

Toxicokinetic parameters:

half-life 2nd: 36 +/- 2 min in the rat (literature data)

Metabolites identified:

not measured

1) Toxicokinetic
The elimination was linear in the plot Log (blood formate) versus time over the entire sampling time, i.e. 90 to 300 minutes after dosing. The calculated half-life was: t_1/2= 87 ± 18 minutes.

(According to Eells et al. (1981) the elimination of formate from blood was more rapid in the rat, with  t_1/2= 36 ± 2 minutes.)

2) Hepatic folates(coenzymes)
The levels of hepatic folates were extremely low in pigs compared to rodents, monkey, and human:

	Species
	Pig (n=8)	Mouse # (n=4)	Rat # (n=6)	Monkey # (n=7)	Human # (n=5)
H4folate	3.3±1.1	42.9±1.2	11.4±0.8	7.4±0.8	6.5±0.3
5-CH3-H4folate	1.0±0.2	11.6±0.4	9.3±0.6	7.6±0.6	6.0±0.7
HCO-H4folate	0.7±0.1	6.4±0.6	4.6±1.3	10.5±0.8	3.3±0.5
Total folate	5.1±1.2	60.9±2.1	25.3±0.9	25.5±1.2	15.8±0.8

 

Values expressed as: nmol of folate/g liver; means ± SEM
# = data from Johlin et al. (1987).


3) Hepatic folate related enzymes
The activities of hepatic enzymes involved in folate reactions were lower in pigs compared to rats.

Enzyme	Pig	n	Rat	n
10-HCO-H4-folate dehydrogenase #	5.8±0.2	5	12.0±0.4***	5
S-adenosylmethionine  §	88.1	2	119.5±5.5	5

 

Values expressed as mean ± SEM.
# = values expressed as nmol productformed/min/mg protein.
§ = values expressed as µmol/g liver.
*** = p<0.001.

 

Conclusions:

The pig, compared to rodents, monkey and humans, has extremely low levels of folates and low levels of key enzyme in the folate pathway. The pig's ability to dispose of formate was extremely limited.

Executive summary:

Formate metabolism was examined in young swine (6 animals) which received sodium formate by intraperitoneal injection (500 mg/kg bw; 10 000 dpm/mg; radiolabel [¹⁴C]). Blood was withdrawn and centrifuged at 90, 180, 240, and 300 min after dosing, and radioactivity was counted in the protein free supernatant. Additionally, the concentration of folate coenzymes and related enzymes was examined in pig and rat liver.

 

The elimination from pig blood followed first order kinetics, as a linear curve was obtained in the plot Log (blood formate) versus time over the entire sampling time, i.e. 90 to 300 minutes after dosing. The calculated half-life was t_1/2= 87 ± 18 minutes. Thus, elimination was much slower than in the rat where the corresponding value was t_1/2= 36 ± 2 minutes according to Eells et al. (1981).  

 

The slow elimination in the pig corresponds with a much lower level of hepatic enzymes involved in formate metabolism in the pig compared to the rat, i.e. levels of 10-HCO-H4-folate dehydrogenase (5.8 nmol product formed/min/mg protein in the pig versus 12.0 in the rat; p≤0.001) and of S-adenosylmethionine (88 nmol product formed/min/mg protein in the pig versus 120 in the rat). The hepatic folate coenzyme levels were also low in the pig compared to other species. The mean total hepatic folate coenzyme level was 5.1 nmol of folate/g liver in pigs, 15.8 in humans, approx. 25 in rats and monkeys, and 61 in mice.

 

The results indicate that the pig, compared to rodents, monkey and humans, has extremely low levels of folates and low levels of key enzyme in the folate pathway. The pig's ability to dispose of formate was extremely limited and slower than that observed in rats, monkeys or humans. The results suggest that the pig may be a suitable model for studying formate metabolism (Makar, 1990).

 

The study is valid and acceptable for assessment.

Reference 10

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well documented and acceptable for assessment. Review article, summarising pre-guideline studies.

Objective of study:

excretion

Principles of method if other than guideline:

Examination of urinary formate excretion following oral sodium formate uptake

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Na-Formiat

Radiolabelling:

no

Species:

dog

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

no data

Route of administration:

oral: feed

Vehicle:

other: feed

Duration and frequency of treatment / exposure:

12 days in one dog
3-4 days in 3 dogs (animals refused further doses)

Dose / conc.:

5 other: g/animal

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: 24-h urine was collected from animals receiving 5 g sodium formate

Statistics:

not required

Details on excretion:

38-40% of the daily dose was excreted in the 24-hour urine.

Conclusions:

Interpretation of results (migrated information): other: there is a bioaccumulation potential
In the dog, urinary formate excretion was much higher than in the rat, indicating a slower metabolism in the dog.

Executive summary:

In a pre-guideline study, the urinary excretion of formate was examined in 4 dogs receiving 5 g sodium formate with the feed for 3 -12 days. 38 -40% of the daily dose were found in the 24 -hour urine (Malorny, 1969).

 

 

Reference 11

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Objective of study:

metabolism

Principles of method if other than guideline:

Depiction of methanol oxidation and formate metabolism

Specific details on test material used for the study:

Methanol and its metabolites including formic acid and formate.

Species:

other: comparison between several species

There are both similarities and species specific differences in the metabolic pathways involved in methanol oxidation in primates and rodents.

1) Methanol oxidation
Primates rely entirely on the activity of alcohol dehydrogenase, whereas catalase perfoms this function in rodents. Despite this difference, this first 

metabolic  step proceeds at similar rates in non-human primates and rodents.

Methanol oxidation
===========================================================
  Primates                   Compound      Rodents
-----------------------------------------------------------
                            CH3OH
Alcohol dehydrogenase                      catalase    
                            HCHO 
Aldehyde dehydrogenase               Aldehyde dehydrogenase 
                      HCOOH / HCOO- + H+  
Folate dependent                           Folate dependent
pathway                                    pathway 
                            CO2
=========================================================== 

2) Formaldehyde is rapidly oxidized (halflife ~1 min) to formic acid in animals or humans.

3) The oxidation of formate to CO2 involves tetrahydro folate (THF). Formyl THF synthetase catalyzes the binding of formate to THF to yield 

10-formyl-THF.  The latter liberates CO2, and the folate moiety is reduced to THF by Formyl THF dehydrogenase. These reactions are 

similar in all species. However,  due to different folate and enzyme levels the reaction rates are different. The rate of formate oxidation
in rats exceeds the maximal rate at which methanol is converted to formate: 1.6 versus 0.9 mmol/kg/hour, respectively. In contrast, when 

primates receive moderately high doses of methanol, the formation of formate can exceed the oxidation of formate: approximately 

1.5 versus 0.75 mmol/kg/hour, respectively. A calculated estimate of the methanol concentration that saturates the human folate pathway is 

11 mM  or 210 mg/kg. There is substantial evidence that formic acid, which readily dissociates to formate and hydrogen ion, is the
metabolite responsible for the visual and metabolic poisoning seen in primates.

Table 1: Mean levels of hepatic folate and folate co-enzymes (nmol/g Liver ± Standard Error [SE]) in various species:
===========================================================
                                    Species
                        -----------------------------------
                        Mouse    Rat      Human    Monkey
-----------------------------------------------------------
Formyltetrahydro-    6.4±0.6   4.6±1.3  3.3±0.5   10.5±0.8*
folate                         5.0±1.2* 

Tetrahydrofolate    42.9±1.2  11.4±0.8  6.5±0.3    7.4±0.8* 
                             12.6±1.1*

5-methyltetrahydro- 11.6±0.4   9.3±0.6  6.0±0.7    7.6±1.1*
folate                         9.4±1.5*

Total folate        60.9±2.1  25.3±0.9 15.8±0.8   25.5±1.2*
                              26.9±3.3*
===========================================================
N = 4-7 subjects per group.
Data are from Johlin et al. (1987) 

* data from Black et al. (1985).
   


Table 2: Mean activities of hepatic folate-dependent enzymes (nmol/min/mg Protein ± SE) in various species:
===========================================================
                                    Species
                        -----------------------------------
                         Rat         Human        Monkey
-----------------------------------------------------------
10-Formyltetrahydro-   65.9±5.0     75.0±8.7   142±16
folate synthetase      41±3*                    184±14*

10-Formyltetrahydro-   88.3±11.7    23.0±2.2    33.0±4.0
folate dehydrogenase   26.0±1.0*                52.6±2.3*

Serine hydroxymethyl-  10.8±0.6     18.5±0.7   17.1±0.7* 
transferase             9.4±1.1*

Tetrahydrofolate       19.8±1.3     0.74±0.17   4.1±0.7*
reductase              20.3±2.2*

5,10-Methylenetetra-   1.21±0.07    0.42±0.07   0.22±0.02*
hydrofolate reductase  1.00±0.05*

Methionine synthase    0.09±0.007   0.10±0.008  0.09±0.012*
                       0.08±0.014*
===========================================================
N = 3-9 subjects per group.
Data are from Johlin et al. (1987) 

* data from Black et al. (1985).

Conclusions:

Interpretation of results (migrated information): other: no formate bioaccumulation in rodents; bioaccumulation in humans possible following ingestion of methanol or formate salts
Other than in rodents, formate may accumulate in primates under certain conditions due to their lower rates of formate oxidation.

Executive summary:

Through several steps, methanol can be oxidized to carbon dioxide in the liver of rodents and primates. The first oxidation to formaldehyde proceeds at similar rates in primates and rats. Formaldehyde is then rapidly oxidized (half-life ~ 1 minute) to formic acid, i.e. formate + H+. Finally, formate is primarily oxidized to carbon dioxide and water in mammals through a tetrahydrofolatedependent pathway.

 

Formate combines with tetrahydrofolate enzymatically to form 10-formyl tetrahydrofolate. Through another enzyme reaction, 10-formyl tetrahydrofolate is oxidized to carbon dioxide and tetrahydrofolate. The availability of tetrahydrofolate, derived from folic acid in the diet, is the major determinant of the rate of formate metabolism. In primates, the folate-mediated oxidation of formate proceeds at one-half the rate observed in rats.

 

The rate of formate oxidation in rats exceeds the maximal rate at which methanol is converted to formate: 1.6 versus 0.9 mmol/kg/hour, respectively. In contrast, when primates receive moderately high doses of methanol, the formation of formate can exceed the oxidation of formate: approximately 1.5 versus 0.75 mmol/kg/hour, respectively. A calculated estimate of the methanol concentration that saturates the human folate pathway is 11 mM or 210 mg/kg.  There is substantial evidence that formic acid, which readily dissociates to formate and hydrogen ion, is the metabolite responsible for the visual and metabolic poisoning seen in primates. In studies where severely toxic or lethal doses were administered, the development of acidosis coincided with the accumulation of formic acid in blood with a parallel decrease of bicarbonate in plasma. In monkeys, it has been demonstrated that inhibition of tetrahydrofolate generation specifically affects formate oxidation, but not methanol disappearance. Decrease in the folate metabolic pool prolongs blood levels of formate by decreasing the rate at which formate combines with tetrahydrofolate.

 

There are significant difernces between species regarding levels and activities of folate and folate enzymes. High levels are found in rodent liver (mouse and rat), whereas levels are significantly lower in humans and monkeys. Therefore, unlike in rodents, formate may accumulate in primates under certain conditions due to their lower rates of formate oxidation (NTP, 2002).

Reference 12

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well documented and acceptable for assessment. Review article, summarising pre-guideline studies.

Objective of study:

metabolism

Principles of method if other than guideline:

Blood formate levels and pH following infusion of sodium formate and formic acid into the dog

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Na-Formiat; Ameisensäure

Species:

dog

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

- Species: dog.
- Body weight: mean 12.5 kg.
- Number: 6 per test substance

Route of administration:

intravenous

Details on exposure:

Test substance: sodium formate and formic acid. 

Duration and frequency of treatment / exposure:

4 hour(s)

Dose / conc.:

81 mg/kg bw (total dose)

Remarks:

in terms of sodium formate

Dose / conc.:

54 mg/kg bw (total dose)

Remarks:

in terms of formic acid

No. of animals per sex per dose / concentration:

6 per test substance

Control animals:

no

Details on dosing and sampling:

- Route: Intravenous infusion.
- Rate: 8 ml/min.
- Doses: 1.17 mmol/kg.
- Dosing solutions:
a) 0.2 M sodium formate in Ringer solution, pH 6.89.
b) 0.2 M formic acid in Ringer solution, pH 2.35.

Toxicokinetic parameters:

half-life 1st: 77 min

Metabolites identified:

no

1) Infusion of 0.2 mM Formic Acid into the dog
i) Acidosis
Infusion of 0.2 mM formic acid caused a metabolic acidosis, substantiated  by a decrease of the blood pH, which was reversible within 4 hours: 
pH 7.45 at start of infusion;
pH 7.30 at end of infusion;
pH 7.38 at 60 min after end of infusion;
pH 7.38 at 120 min after end of infusion;
pH 7.42 at 240 min after end of infusion;

ii) Blood levels 
202.8 mg/l were reached at the end of the infusion and declined  exponentially until reaching normal levels (9 mg/l) 4 hours after the  infusion had ended.

iii) Half-life time
The t1/2 was calculated to be 77 min.

iv) Metabolites
Formation of methemoglobin was not detected. Formate oxidation rate was  maximal approx. 1 hour after the infusion had ended, as evidenced by the  rate of CO2 exhalation.


2) Infusion of 0.2 mM Sodium Formate
i) Acidosis
The pH was less markedly decreased (to only 7.39) and returned to normal  within 180 min after the infusion had ended.

ii) Blood levels
182.5 mg/l were reached at the end of the infusion and declined  exponentially until reaching normal levels (9.8 mg/l) 4 hours after the  infusion had ended.

iii) Half-life time
The t1/2 was calculated to be similar to the infusion of formic acid.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Formate metabolism occurs mainly in the liver. The metabolic rate is generally rapid in mammals, but this is clearly species specific.

Executive summary:

 

The effect of sodium formate and of formic acid, both given as intravenous infusions into 6 dogs/test substance, on blood formate levels and pH value was examined in a pre-guideline study. The infusion of 0.2 mM sodium formate caused a slight decrease of blood pH, whereas a 0.2 mM formic acid caused a marked acidosis which was reversible within 4 hours. Methemoglobin concentration did not increase. Formate plasma concentrations declined exponentially, and normal background values were reached within 3 to 4 hours after the infusion of formic acid or sodium acid had ended. The calculated half-live (T_1/2) was 77 minutes in the dog, and it was similar for both, sodium formate and formic acid.

Metabolism of formate is relatively slow in carnivores compared to other species  as can be seen from the plasma half-life times T_1/2: rat (12 min), Guinea pig (22 min), rabbit (32 min), cat (67 min), and dog (77 min). In rabbits, the T_1/2raised from 35 min to 130 min when the metabolism in liver was inhibited, i.e. formate metabolism occurs predominantly in the liver. Moreover, folic acid was suggested to play a major role. Methemoglobin was not detected to increase in dosed animals. Based on the above and several long term, reproduction and teratogenicity studies, the author generally concluded that no adverse health effects were expected from the use of formic acid as food preservative at concentrations and daily doses as listed in the respective national regulation (Lebensmittelgesetz, December 21st, 1958; concentration up to 1 g/kg food, and daily doses up to 1 g/day) (Malorny, 1969).

 

 

Description of key information

The toxicokinetic behaviour, metabolism and elimination of formic acid, formate salts and methanol as a formic acid precursor has been extensively studied in several species including human

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

The toxicokinetic behaviour, metabolism and elimination of formic acid, formate salts and methanol as a formic acid precursor has been extensively studied in several species including humans, and there are significant species differences in the rate of formate oxidation which need to be taken into 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 the read-across of results obtained with different forms of formates.

Sodium formate 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

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 behaviour of potassium diformate and formic acid solutions from titre curves indicate that the equilibrium in equation [2] is in favour of potassium diformate at pH < 4 and at concentrations below 0.1 % (Hydro Research Centre, 1997).

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

At pH values of 4-5, 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; Hanzliket 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.

Discussion on absorption rate

Dermal absorption is considered likely to be very low, but no study is known to exist. Dermal absorption is therefore considered to be equivalent to be oral absorption for the purposes of DNEL derivation. In the absence of specific data, inhalation absorption is considered to be twic that of oral absorption.