Potassium hydrogencarbonate

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

A study on fertility, e. g. a 1- or 2- generation study, is not available for potassium hydrogencarbonate. However, a study on fertility is scientifically unjustified. There are no indications on an intrinsic toxicity to reproduction of potassium hydrogencarbonate from the results of reliable developmental toxicity and teratogenicity studies performed on the source substance potassium carbonate, reliable repeated dose toxicity studies with macroscopic and histological examination of the male and female reproductive organs (epididymides, testes, ovaries, and uterus) performed with potassium hydrogencarbonate and available information from assessments carried out within the OECD work on investigation of high production volume chemicals on compounds which have a carbonate or a potassium moiety. Further on, based on chemistry considerations of the structure of potassium hydrogencarbonate, no reproductive toxicity is expected to occur because potassium hydrogencarbonate will not influence the natural K+ or CO32- level in the body and will not reach the foetus nor reach male and female reproductive organs under normal handling and use conditions.

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A study on fertility, e. g. a 1- or 2- generation study, is not available for potassium hydrogencarbonate. However, a study on fertility is scientifically unjustified. Long-term studies on potassium hydrogencarbonate are available, in which reproduction organs have been evaluated. In these studies the macroscopically and histopathologically evaluated reproductive organs epididymides, testes, ovaries, and uterus were free of treatment related effects, even at lifetime (30 months) treatment with dose levels far exceeding the guideline limit dose for one or two generation studies of 1000 mg/kg body weight/day (for details see Chapter 5.6. Repeated dose toxicity).

Further on, based on chemistry considerations of the structure of potassium hydrogencarbonate, no reproductive toxicity is expected to occur because potassium hydrogencarbonate will not influence the natural K⁺ or HCO₃^- level in the body and will not reach the foetus nor reach male and female reproductive organs under normal handling and use conditions.

Absence of intrinsic toxic properties of potassium hydrogencarbonate is generally taken for granted, which is proved by its long-standing safe use in food - including foodstuffs for infants and children - and pharmaceuticals and its GRAS (generally recognized as safe) status in the. In addition, available information from assessments carried out within the OECD work on investigation of high production volume chemicals on compounds which have a carbonate or a potassium moiety gives no indication on an intrinsic toxicity to reproduction of potassium or carbonate either. OECD SIDS Initial Assessment Reports are e. g. available for Bicarbonate special, Sodium carbonate, Sodium bicarbonate, Ammonium hydrogencarbonate which have a carbonate moiety and on Potassium chloride, Potassium hydroxide or Potassium methanolate, which have a potassium moiety (reports are published via internet (http: //www. oecd. org/document/63/0,3343, en_2649_34379_1897983_1_1_1_1,00. html). None of these compounds are considered to have the potency to be toxic to reproduction.

Potassium and carbonate are essential constituents and two of the most abundant ions in all animal species. In adult humans, the total body potassium is approx. 3.5 mol (135 g). 98 % of this is located intracellular (150 mmol/l), the extracellular potassium concentration is approx. 4 mmol/l.

 

The metabolism and mechanisms of action of potassium and carbonate are well reviewed in standard textbooks on pharmacology and physiology.

 

About 90 % of the ingested dose of potassium is absorbed by passive diffusion in the membrane of the upper intestine. Potassium is distributed to all tissues where it is the principal intracellular cation. Insulin, acid-base status, aldosterone, and adrenergic activity regulate cellular uptake of potassium.

The majority of ingested potassium is excreted in the urine via glomelural filtration. The distal tubules are able to secrete as well as reabsorb potassium, so they are able to produce a net secretion of potassium to achieve homeostasis in the face of a potassium load due to abnormally high levels of

ingested potassium. About 15 % of the total amount of potassium excreted is found in faeces.

Excretion and retention of potassium is mainly regulated by the main adrenal cortical hormones.

Normal homeostatic mechanisms controlling the serum potassium levels allow a wide range of dietary intake. The renal excretory mechanism is designed for efficient removal of excess K, rather for its conservation during deficiency. Even with no intake of K, humans lose a minimum of 585-1170 mg K per day. However, the distribution of potassium between the intracellular and the extracellular fluids can markedly affect the serum potassium level without a change in total body potassium. K+ is the principal cation mediating the osmotic balance of the body fluids. In animals, the

maintenance of normal cell volume and pressure depends on Na+ and K+ pumping. The K+/Na+separation has allowed for evolution of reversible transmembrane electrical potentials essential fornerve and muscle action in animals, and both potassium and chloride are important in transmissionof nerve impulses to the muscle fibers.

Potassium transport through the hydrophobic interior of a membrane can be facilitated by a numberof natural compounds that form lipid-soluble alkali metal cation complexes. Potassium serves thecritical role as counterion for various carboxylates, phosphates and sulphates, and stabilizesmacromolecular structures (OECD SIDS, 2001).

 

The bicarbonate buffer system described by the following equation:

H2O + CO2 <=> H2CO3 <=> H+ + (HCO3)-

is the major extracellular buffer in the blood and the interstitial fluid of vertebrates. The blood plasma of man normally has a pH of 7.40. Should the pH fall below 7.0 or rise above 7.8, irreversible damage may occur. Compensatory mechanisms for acid-base disturbances function to alter the ratio of (HCO3)- to PCO2, returning the pH of the blood to normal. Thus, metabolic acidosis may be compensated for by hyperventilation and increased renal absorption of (HCO3)-. Metabolic alkalosis may be compensated for by hypoventilation and the excess of (HCO3)- in the urine. Renal mechanisms are usually sufficient to restore the acid-base balance (OECD SIDS, 2002).

 

No fertility study has been localised for potassium hydrogencarbonate or related substances. However, the maximum plasma concentration of potassium and carbonate is efficiently and tightly regulated by renal elimination. A significant increase in the potassium concentration in the extracellular fluid will only occur after high potassium intake or in patients with severely reduced kidney function.

 

No effects of exposure potassium hydrogencarbonate on gonadal function can be expected if the plasma concentrations are within the normal range, as neither potassium nor carbonate accumulates in the body. Based on the extensive amount of knowledge on regulation and effects of potassium and carbonate in the human body, no further testing of fertility is required.

 

References

OECD SIDS, 2001. Potassium chloride.SIDS Initial Assessment Report for 13th SIAM. UNEP Publications.

 

OECD SIDS, 2002. Sodium bicarbonate.SIDS Initial Assessment Report for 15th SIAM. UNEP Publications.

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity studies performed with closely related read-across substance potassium carbonate in rats and mice by oral route are available. Although the studies have been performed prior to implication of the guidelines they are well performed and documented and comparable to recent guideline studies with the exception that the nowadays required highest dose of 1000 mg/kg bw was not included. None of these studies gave indications on intrinsic toxic effects of potassium carbonate on reproduction. Further on, based on chemistry considerations of the structure of potassium hydrogencarbonate, no reproductive toxicity is expected to occur because potassium hydrogencarbonate will not influence the natural K+or HCO3-level in the body and will not reach the foetus nor female reproductive organs under normal handling and use conditions. 

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across hypothesis is based on transformation of the target and source substances to common compounds (scenario 1 of the Read-Across Assessment Framework (RAAF), ECHA, March 2017 - transformation to common compounds). The target substance potassium hydrogen carbonate as well as the source substance potassium carbonate dissociate in aqueous media to potassium and carbonate.

For further details, please refer to the Justification for Read-Across attached in Iuclid Chapter 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to the Justification for Read-Across attached in Iuclid Chapter 13.

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to the Justification for Read-Across attached in Iuclid Chapter 13.

4. DATA MATRIX
Please refer to the Justification for Read-Across attached in Iuclid Chapter 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

not tested up to current limit dose

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: virgin adult
- Weight at study initiation: 75 - 78 g
- Fasting period before study: no data
- Housing: gang-housed in disposable plastic cages
- Diet: ad libitum
- Water: tap water, ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled, record available in study report
- Humidity (%): controlled, record available in study report
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: gavage

Vehicle:

water

Duration of treatment / exposure:

day 6 to 15 of gestation

Frequency of treatment:

once daily

Duration of test:

until day 17 of gestation

No. of animals per sex per dose:

22 to 25 animals

Control animals:

yes, sham-exposed

other: second control group treated with 150 mg Aspirin/kg bw

Statistics:

Not reported

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Refer to remarks on results

Dose descriptor:

NOEL

Effect level:

290 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Abnormalities:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Refer to remarks on results

Dose descriptor:

NOEL

Effect level:

290 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Dose descriptor:

NOEL

Effect level:

290 mg/kg bw/day

Basis for effect level:

other: fetotoxicity

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

There were no treatment-related maternal or developmental toxic effects observed in the study.
This outcome is applicable also to the target substance Potassium hydrogencarbonate.

Reference 2

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across hypothesis is based on transformation of the target and source substances to common compounds (scenario 1 of the Read-Across Assessment Framework (RAAF), ECHA, March 2017 - transformation to common compounds). The target substance potassium hydrogen carbonate as well as the source substances potassium carbonate dissociate in aqueous media to potassium and the respective anion.

For further details, please refer to the Justification for Read-Across attached in Iuclid Chapter 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to the Justification for Read-Across attached in Iuclid Chapter 13.

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to the Justification for Read-Across attached in Iuclid Chapter 13.

4. DATA MATRIX
Please refer to the Justification for Read-Across attached in Iuclid Chapter 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

not tested up to current limit dose

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: virgin adult females
- Weight at study initiation: 221 to 232 g
- Fasting period before study: no data
- Housing: individually in mesh bottom cages
- Diet: ad libitum
- Water: tap water, ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled, record available in study report
- Humidity (%): controlled, record available in study report
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Volume administered: 1 ml/kg bw/day

Details on mating procedure:

Females were mated with young adult males, observation of the vaginal plug was considered day 0 of gestation. One male was not permitted to impregnate more than one female per group.

Duration of treatment / exposure:

day 6 to 15 of gestation

Frequency of treatment:

once daily

Duration of test:

until day 20 of gestation

No. of animals per sex per dose:

22 to 25 animals

Control animals:

yes, sham-exposed

other: second control group treated with 250 mg Aspirin/kg bw

Statistics:

Not reported

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Refer to remarks on results

Dose descriptor:

NOEL

Effect level:

180 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Abnormalities:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Refer to remarks on results

Dose descriptor:

NOEL

Effect level:

180 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Dose descriptor:

NOEL

Effect level:

180 mg/kg bw/day

Basis for effect level:

other: fetotoxicity

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

There were no treatment-related maternal or developmental toxic effects observed in the study.
This outcome is applicable also to the target substance Potassium hydrogencarbonate.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No developmental toxicity / teratogenicity study on potassium hydrogencarbonate available. However, reliable, adequate and relevant studies on read-across substances potassium carbonate are available. Although the studies have been performed prior to implication of the guidelines they are well performed and documented and comparable to recent guideline studies with the exception that the nowadays required highest dose of 1000 mg/kg bw was not included. A justification for read-across is attached to iuclid section 13.

Oral teratogenicity studies on potassium carbonate performed on two species (rat and mouse) and an inhalative teratogenicity study on a potassium carbonate-based technical formulation performed on rats available. In these studies there were no indications on any reproductive effects.

Potassium carbonate was administered daily via oral intubation to pregnant mice and rats at doses ranging from 2.9 to 290 mg/kg bw and 1.8 to 180 mg/kg bw respectively during days 6-15 of gestation. The test substance had neither effects on mortality, body weight gain and the macroscopy of the urogenital tracts of the dams nor effects on numbers of corpora lutea, live litters, implantations, resorptions, live and dead fetuses, the sex ratio of the fetuses or the average fetus weight. Soft tissue and skeletal anomalies noted in the experimental group did not differ from anomalies occurring in sham-treated controls. Therefore, the NOEL for maternal toxicity, developmental toxicity and teratogenicity in these studies is 290 mg/kg bw for mice and 180 mg/kg bw for rats (highest doses tested) (Food and Drug Research Laboratories, 1975). Also, a potassium carbonate-based scrubbing solution as used in petroleum refineries did not appear to be a developmental toxicant in rats. Sprague-Dawley rats were whole body exposed to the used scrubbing solution “Cartacarb” at concentrations of 0.05, 01.0.2 and 0.3 mg/L for 6 h/d on days 6 to 19 of pregnancy. “Catacarb” is an alkaline solution consisting primarily of potassium carbonate and low concentrations of borate, diethanolamine, and metavanadate salts, used to remove acidic gases from refinery gas streams by chemical absorption (analytical composition of the used “Catacarb” solution collected from a hydrotreating unit of a refinery: pH 9.9, 30.8% potassium carbonate, 65.1% water, 1.6% diethanolamine, 0.4% potassium borate (as boron), 0.3% potassium metavanadate (as vanadium), and 6.7 ppm chromium, 8.4 ppm molybdenum and 4.5 ppm nickel).

Maternal toxicity was exhibited in the 0.3 mg/L group, including signs of respiratory tract impairment, reduced body weight and food consumption, and one animal died. The only fetal effect seen was a delayed mineralization of sternal elements at the maternal toxic concentration of 0.3 mg/L. The incidence of fetuses (14 fetuses vs. 6 fetuses in control) but not the litter incidence (2/22 litters vs. 5/23 litters in control) with sternebrae 5 and/or 6 unossified was increased in this group. The increase in fetuses with delayed mineralization of sternal elements in this dose group was primarily attributable to two litters conceived by the two most severely affected mothers in the group. The delayed mineralization is most probably a consequence of the maternal toxicity and no indication on an intrinsic developmental toxic activity of the formulation. The NOAEC for maternal toxicity and the NOEC for developmental toxicity is 200 mg scrubbing solution (corresponding to 62 mg potassium carbonate) /m³ and the NOEC for teratogenicity is 300 mg scrubbing solution (corresponding to 92 mg potassium carbonate) /m³ (highest concentration tested) (Bui et al., 1998b).

Although potassium carbonate was not tested up to the limit dose of current guidelines, no potential for teratogenicity is expected, sincePotassium and carbonate are essential constituents and two of the most abundant ions in all animal species. In adult humans, the total body potassium is approx. 3.5 mol (135 g). 98 % of this is located intracellular (150 mmol/l), the extracellular potassium concentration is approx. 4 mmol/l.

 

The metabolism and mechanisms of action of potassium and carbonate are well reviewed in standard textbooks on pharmacology and physiology.

 

About 90 % of the ingested dose of potassium is absorbed by passive diffusion in the membrane of the upper intestine. Potassium is distributed to all tissues where it is the principal intracellular cation. Insulin, acid-base status, aldosterone, and adrenergic activity regulate cellular uptake of potassium.The majority of ingested potassium is excreted in the urine via glomelural filtration. The distal tubules are able to secrete as well as reabsorb potassium, so they are able to produce a net secretion of potassium to achieve homeostasis in the face of a potassium load due to abnormally high levels ofingested potassium. About 15 % of the total amount of potassium excreted is found in faeces.

Excretion and retention of potassium is mainly regulated by the main adrenal cortical hormones.

Normal homeostatic mechanisms controlling the serum potassium levels allow a wide range of dietary intake. The renal excretory mechanism is designed for efficient removal of excess K, rather for its conservation during deficiency. Even with no intake of K, humans lose a minimum of 585-1170 mg K per day. However, the distribution of potassium between the intracellular and the extracellular fluids can markedly affect the serum potassium level without a change in total body potassium. K+ is the principal cation mediating the osmotic balance of the body fluids. In animals, themaintenance of normal cell volume and pressure depends on Na+ and K+ pumping. The K+/Na+separation has allowed for evolution of reversible transmembrane electrical potentials essential fornerve and muscle action in animals, and both potassium and chloride are important in transmissionof nerve impulses to the muscle fibers.

Potassium transport through the hydrophobic interior of a membrane can be facilitated by a numberof natural compounds that form lipid-soluble alkali metal cation complexes. Potassium serves thecritical role as counterion for various carboxylates, phosphates and sulphates, and stabilizesmacromolecular structures (OECD SIDS, 2001).

 

The bicarbonate buffer system described by the following equation:

H2O + CO2 <=> H2CO3 <=> H+ + (HCO3)-

is the major extracellular buffer in the blood and the interstitial fluid of vertebrates. The blood plasma of man normally has a pH of 7.40. Should the pH fall below 7.0 or rise above 7.8, irreversible damage may occur. Compensatory mechanisms for acid-base disturbances function to alter the ratio of (HCO3)- to PCO2, returning the pH of the blood to normal. Thus, metabolic acidosis may be compensated for by hyperventilation and increased renal absorption of (HCO3)-. Metabolic alkalosis may be compensated for by hypoventilation and the excess of (HCO3)- in the urine. Renal mechanisms are usually sufficient to restore the acid-base balance (OECD SIDS, 2002).

 

No fertility study has been localised for potassium carbonate or related substances. However, the maximum plasma concentration of potassium and carbonate is efficiently and tightly regulated by renal elimination. A significant increase in the potassium concentration in the extracellular fluid will only occur after high potassium intake or in patients with severely reduced kidney function.

 

No effects of exposure potassium carbonate on gonadal function can be expected if theplasma concentrations are within the normal range, as neither potassium nor carbonateaccumulates in the body. Based on the extensive amount of knowledge on regulation and effects of potassium and carbonate in the human body, no further testing of developmental toxicity is required.

 

References

OECD SIDS, 2001. Potassium chloride.SIDS Initial Assessment Report for 13th SIAM. UNEP Publications.

 

OECD SIDS, 2002. Sodium bicarbonate.SIDS Initial Assessment Report for 15th SIAM. UNEP Publications.

 

 

Justification for classification or non-classification

There is no evidence for an intrinsic toxicity to reproduction of potassium hydrogencarbonate from the results of reliable developmental toxicity and teratogenicity studies on mice and rats performed with the closely related read-across substance potassium carbonate, reliable repeated dose toxicity studies with macroscopic and histological examination of the male and female reproductive organs (epididymides, testes, ovaries, and uterus) performed with potassium hydrogencarbonate itself and available information from assessments carried out within the OECD work on investigation of high production volume chemicals on compounds which have a carbonate or a potassium moiety. Further on, based on chemistry considerations on the structure of potassium hydrogencarbonate and potassium hydrogencarbonate, no toxicity to reproduction is expected.

Therefore no classification is required for toxicity to reproduction according to CLP Regulation (EC) No 1272/2008.