Potassium carbonate

Carcinogenicity

Description of key information

No reliable studies on carcinogenicity of potassium carbonate are available. Reliable oral studies on closely related read-across substance potassium hydrogencarbonate give no indications on intrinsic carcinogenicity relevant to humans. 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 a carcinogenic potency of potassium or carbonate either.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

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

Adequacy of study:

supporting 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 carbonate as well as the source substances potassium hydrogencarbonate and potassium chloride 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 source

Reason / purpose for cross-reference:

read-across: supporting information

Principles of method if other than guideline:

Non-guideline 30-month-study to examine the effects of died-induced acid-base disturbances. Diets were supplemented with high amounts of potassium hydrogencarbonate (2% or 4%, base-forming diets), ammonium chloride (2.1% acid forming diet) or potassium chloride (3%, neutral diet, providing K+ and Cl- in amounts equimolar to those in the 4% potassium hydrogencarbonate and the 2.1% ammonium chloride diet, respectively).

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: feed

Duration of treatment / exposure:

18 months, 30 months

Remarks:

Doses / Concentrations:
2 and 4 % in the diet
Basis:
nominal in diet

No. of animals per sex per dose:

50

Control animals:

yes, plain diet

Clinical signs:

no effects observed

Description (incidence and severity):

- Clinical signs: no treatment-related abnormalities in condition or behaviour; there was only the usual random incidence of ageing symptoms that occur in this strain of rats when maintained over a period of time
- Grossly visible or palpable masses: no treatment-related effects

Description (incidence):

- Mortality and time of death: mortality rate was not affected by treatment; males were killed in week 122 because mortality in the low-dose group reached 70%,; females were killed after completion of this study in week 131; overall mortality rates at termination in control, low- and high-dose group were 62, 70, and 56% for males, respectively, and 69, 65, and 72% for females, respectively

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

- mean body weights decreased in males and females of the high dose group (decrease in the range of 4 to 10%, no exact data given); body weights were also statistically significantly decreased in females of the low dose group at various stages of the study (no further data given)

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

- ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX:
-- males: 1285 and 2667 mg/kg bw/d (9.3 and 19.3 mmol/kg bw/d)
-- females: 1576 and 3331 mg/kg bw/d (11.4 and 24.1 mmol/kg bw/d)
(recalculation of dose from data given in mmol/kg bw/d (molecular weight=138.21 mg/mmol) )

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

- in the 2% and the 4% dose group approximately 10% and 40% increased, respectively

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

- no consistent or treatment-related effects on red blood cell variables, clotting potential or total and differential white blood cell counts

Clinical biochemistry findings:

not examined

Description (incidence and severity):

- Blood gas analysis: dose-related increase in base excess, associated with higher blood pH and bicarbonate concentrations
- Clinical biochemistry: not performed

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

- Urine parameter of non-fasted animals: urine volume increased in both sexes of the high dose group, in females, this finding was no longer apparent in the later stages of the study, which may have been due to the high values obtained in the control group; the urinary density did not show consistent differences but tended to be decreased in males of the high dose group; potassium excretion increased in both sexes in both dose groups; urinary sodium excretion tended to be relatively high at various occasions in rats fed 4% potassium hydrogencarbonate, which may be ascribed to the natriuretic effect of high potassium intake but the figures showed large variations; no treatment related effects on excretion of calcium, phosphate, sulphate, gamma glutamyl transferase or hydroxyproline
- Urinary pH and acid indices: pH increased in both dose groups, net acid excretion (= ammonium ion (NH4+) excretion + urinary titratable acidity - bicarbonate excretion) considerable decreased in both sexes of the high dose group, and to a lesser extend in the low dose group
- Concentrating ability of the kidneys: the renal concentration test (no food and water available prior to and during urine sampling) showed a slightly increased volume associated with a somewhat decreased density of the urine in males of both dose groups and in females of the high dose group in week 77; brownish discoloration of the urine and haematuria, as detected with urinary test stripes and by microscopic examination of the urinary sediment were occasionally increased, but there were no consistent or dose-related differences in incidence or severity of haematuria among the groups; the occurrence of crystals was not affected in any group
- Calcium content in femur: no treatment-related effects

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

- Kidney weights: relative kidney weights in females tendentiously but neither dose related nor statistically significant increased, relative kidney weights in males tendentiously and dose related but not statistically significant decreased
- Further examined organ weights: there were no consistent or treatment-related changes in the weights of adrenals, brain, testes, liver, spleen, ovaries, pituitary, thyroid, or heart

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

- Macroscopic examination of the urine bladder: thickening and/or induration of the urinary bladder wall, irregular serosal surface and/or luminal dilatation. Tumorous enlargement of the bladder was seen in one female animal of the 4% ; the mass filled the bladder lumen and was confined to the bladder, i.e. it did not show invasion into, or adhesions with, adjacent tissues. Bladder stones were not observed.
- Macroscopic examination of further organs and tissues: no significant differences among the treatment groups and the controls

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

- Adrenals: in both sexes of both dose groups, the zona glomerosa was distinctly wider than in controls, the cells in this area were enlarged and showed a finely vacuolar cytoplasm (47-50 animals per sex and dose examined (both survivors and intercurrent deaths), findings in the low and high dose group in 22 (significant) and 41 males (significant, control: 4), respectively, and 8 (not significant) and 32 females (significant, control: 7), respectively. This microscopic finding was interpreted by the study authors as adaptive response to chronic simulation of the adrenal cortex by potassium cations.
- Kidneys: in both sexes of both dose groups, oncocytic tubules but no treatment-related significant severe or very severe nephrosis or urothelial hyperplasia in the pelvis (47-50 animals per sex and dose examined (both survivors and intercurrent deaths), findings in the low and high dose group in 32 (significant) and 36 males (significant, control: 18), respectively, and 22 (significant) and 22 females (significant, control: 1), respectively. The oncocytic tubules were characterised by tubules lined with, often hypertrophy, epithelial cells containing eosinophilic granular cytoplasm (oncocytes), often showing a cystically dilated lumen with epithelial cells protruding into the lumen. As discussed by the study authors, oncocytic tubules do occur spontaneously in untreated rat and are commonly observed in aged males, regarded as regenerative hyperplasia or as a functional tubular hyperplasia in order to meet increased work load. The authors suggested that the hydrogen carbonate anion mainly determined the increased occurrence of this lesion.
- Urinary bladder: in both sexes of both dose groups, the incidence of simple epithelial hyperplasia, of papillary and nodular hyperplasia, and of papillomas were increased. However, except of simple hyperplasia , significance was only reach in high dose female group.
-- Cystitis: in 1/48, 0/50 and 0/49 males, and 1/48, 0/48 and 1/47 (not significant) females in the control, the low- and the high-dose group, respectively
-- Simple epithelial hyperplasia in 1/48, 12/50 (significant) and 22/49 (significant) males, and 1/48, 23/48 (significant) and 24/47 (significant) females in the control, the low- and the high-dose group, respectively
-- Papillary epithelial hyperplasia in 0/48, 0/50 and 0/49 males, and 0/48, 2/48 (not significant) and 5/47 (significant) females in the control, the low- and the high-dose group, respectively
-- Nodular epithelial hyperplasia in 0/48, 2/50 (not significant) and 4/49 (not significant) males, and 0/48, 1/48 (not significant) and 11/47 (significant) females in the control, the low- and the high-dose group, respectively
- Reproductive organs: no treatment-related effects (coagulating gland, epididymides, prostate, seminal vesicles, testes, mammary gland, ovaries, uterus, and preputial/clitoral glands examined)
- Further examined organs and tissues: no treatment-related effects

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

- Urinary bladder:
--Transitional-cell papilloma (one or multiple) in 0/48, 4/50 (not significant) and 2/49 (not significant) males, and 0/48, 1/48 (not significant) and 6/47 (significant) females in the control, the low- and the high-dose group, respectively
--Transitional-cell carcinoma in 0/48, 1/50 (not significant) and 1/49 (not significant) males, and 0/48, 1/48 (not significant) and 3/47 (not significant) females in the control, the low- and the high-dose group, respectively
- Total tumour incidence: Apart from preneoplastic and neoplastic lesions in the urinary bladder, there were no treatment-related changes in any specific tumor type among the groups; potassium hydrogencarbonate did neither affect type, incidence and multiplicity of tumours, nor time of tumor appearance and the ratio benign-malignant tumours.

HISTORICAL CONTROL DATA
- Neoplastic alterations of urinary bladder: Historical control data obtained in 18 different chronic (exact duration not mentioned) studies with Wistar rats of the laboratory revealed no papillomas or carcinomas of the urinary bladder in 795 male and 777 female control rats.

Other effects:

no effects observed

Description (incidence and severity):

- Calcium content in femur: no treatment-related effects
- Excretion of calcium and phosphorus in faeces and urine: no treatment-related effects

Dose descriptor:

NOAEL

Effect level:

2 667 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEL

Effect level:

3 331 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

no

Conclusions:

No carcinogenic potential for potassium hydrogencarbonate has been concluded by evaluating the results of this study. By read across the same conclusion can be drawn for potassium carbonate.

Executive summary:

In a 130 -week (30-month) toxicity study potassium hydrogencarbonate (a.i. >99.5%) was administered to 15 Wistar rats, strain SPF Cpb:WU/sex/dose in the diet at dose levels of 0, 2 and 4% (0, 1285 and 2667 mg/kg bw/d (9.3 and 19.3 mmol/kg bw/d) in males, respectively and 0, 1576 and 3331 mg/kg bw/d (11.4 and 24.1 mmol/kg bw/d) in females, respectively, based on body weight and food consumption.

Object of the study was to examine the effects of died-induced acid-base disturbances. Albeit the study was not performed according to a explicit mentioned international guideline, accomplishment and documentation cover a broad range of the requirements of the usual guidelines for repeated dose toxicity studies. The dose level exceeds the guideline limit dose for repeated dose toxicity studies which is 1000 mg/kg bw/d in the low dose group by almost 30 or 60 % and in the high dose group by almost 170 or 230 % for males and females, respectively.

The rats adapted relatively easily to the feeding of these very high doses and were free of treatment related adverse effects relevant to humans. Most treatment related changes seen are an expression of the physiological adaptation to the very high ion intake and regarded as of no toxicological relevance. In the urinary bladder significant preneoplastic and neoplastic histopathological epitelial alterations have developed, which are common findings in rats after long term high dose alkali intakes.The relevance to humans of preneoplastic or neoplastic urinary bladder findings in rats induced by high dose alkali intakes (e.g. as counterions in food additives like artificial sweetener or flavour enhancer) and associated by alkalinization of the urine, elevated urine volumes, altered urine electrolytes composition with or without renal pelvic mineralization or urine precipitation which leads to a cyctotoxic effect on the bladder epithelium with consequent regenerative proliferation and ultimately tumors have been discussed for a long time (e.g. by the International Agency for Research on Cancer as part of the World Health Organization (IARC) in the IARC Monography Vol. 73 (1999) and in the IARC Scientific Publication No 147 (1999) or more recently by the European Food Safety Authority (EFSA) in the option on Aspartam (2006) or a review by Cohen, SM on Thresholds in Genotoxicity and Carcinogenicty: Urinary Bladder Carcinogenisis (2008)). It is widely accepted that these high dose effects are specific to the rat and are of no relevance to humans.

Apart from the discussed preneoplastic and neoplastic histopathological epithelial alterations in the urinary bladder, there were no treatment-related changes in any specific tumor type among the groups; potassium hydrogencarbonate did neither affect type, incidence and multiplicity of tumors, nor time of tumor appearance and the ratio benign-malignant tumours.

The NOAEL relevant to humans is the highest dose tested of 4 % in diet, based on body weight and diet intake corresponding to 2667 mg/kg bw/d (19.3 mmol/kg bw/d) in males and 3331 mg/kg bw/d (24.1 mmol/kg bw/d) in females.

The study has been part of a study set comprising of this 130 -week study, a 4 -week study, a 13 -week study, and a 78 -week (18 -month) study. The dose levels in all studies were 2 and 4% in diet. A summarizing discussion of the results of the whole study set is given in the endpoint summary on repeated dose toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

There is no evidence for an intrinsic carcinogenicity of potassium carbonate relevant to humans obtained from the results of studies on the closely related read across substance potassium hydrogencarbonate and additional 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.

Moreover, there is no evidence for a clastogenic or mutagenic potential of potassium carbonate from reliable studies and based on chemistry considerations on the structure of potassium carbonate, no carcinogenicity is expected.

Therefore, no classification is required for carcinogenicity according to CLP, EU GHS (Regulation (EC) No 1272/2008).

Additional information

No studies on the intrinsic carcinogenicity of potassium carbonate are available. However, based on the approved long use of potassium carbonate in pharmaceutical preparations and foodstuffs with no specific quantity restriction except of the quantum satis principle and the nutritional essentiality of potassium as well as the essential role of carbonate in the body, potassium carbonate can be judged as non-carcinogenic. In addition, reliable studies on closely related read-across substance potassium hydrogencarbonate covering the endpoint carcinogenicity are available and described in more detail in chapter 5.6 Repeated Dose Toxicity. These studies include two long-term studies (18 -months, and 30 -months) in which rats were treated with very high doses of potassium hydrogencarbonate in their feed (2 and 4%). The studies were not performed according to explicitly mentioned international guidelines, but their accomplishment and documentation cover a broad range of the requirements of the usual guidelines for repeated dose toxicity and carcinogenicity studies. Thus, these studies are relevant, reliable and adequate for the purpose of assessing repeated dose toxicity as well as carcinogenicity. Even the low dose level of this study set exceeds the guideline limit dose for repeated dose toxicity studies to a considerable degree, no treatment related toxic effects relevant to humans were seen.

After 18-months and 30-months of treatment few potassium hydrogencarbonate-fed animals showed thickening and/or induration of the urinary bladder wall and irregular serosal surface and/or luminal dilatation of the urinary bladder. At 18 months 1/15 males of the 4% group was found to have a grossly visible bladder mass, which extended into the dorsal prostate. At 30 months tumorous enlargement of the bladder was seen in 1/47 female in the 4% group. Bladder stones were not observed. Microscopic examination of the urinary bladder showed very slight to slight simple epithelial hyperplasia in both dose groups, which was not significant after 4 or 13 weeks of treatment, and became significant after 18 months of treatment in low and high dose males and high dose females, and was also significant after 30 months of treatment in both sexes of both dose groups. Significant papillary epithelial hyperplasia of the urinary bladder was seen in the high dose females treated 18 months and dose independently in the low dose males of this study, and the high dose females treated 30 months, which also showed significant nodular epithelial hyperplasia and transitional-cell papilloma.

The relevance to humans of preneoplastic or neoplastic urinary bladder findings in rats induced by high dose alkali intakes (e. g. as counter ions in food additives like artificial sweetener or flavour enhancer) have been discussed for a long time (e. g. by the International Agency for Research on Cancer as part of the World Health Organization (IARC) in the IARC Monography Vol. 73 (1999) and in the IARC Scientific Publication No 147 (1999) or more recently by the European Food Safety Authority (EFSA) in the option on Aspartam (2006) or a review by Cohen, SM (2008)). Preneoplastic or neoplastic urinary bladder findings in the rat in connection with high dose alkali intakes are in general associated with alkalinization of the urine, elevated urine volumes, altered urine electrolytes composition with or without renal pelvic mineralization or urine precipitation which leads to cytotoxic effect on the rat bladder epithelium with consequent regenerative proliferation and ultimately tumors. It is widely accepted that these high dose effects are specific to the rat and are of no relevance to humans.

In conclusion, there were no treatment-related changes in any specific tumor type among the groups; potassium hydrogencarbonate did neither affect type, incidence and multiplicity of tumors, nor time of tumor appearance and the ratio benign-malignant tumours.

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 a carcinogenic potency 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 a carcinogenic potency relevant to humans.

Thus, there are no indications on a carcinogenic activity of potassium carbonate relevant to humans from reliable studies on the closely related read-across substance potassium hydrogencarbonate or from reliable assessments of ionic substances having a potassium or a carbonate moiety. Moreover, there is no evidence for a clastogenic or mutagenic potential of potassium carbonate from reliable studies. The abiotic dissociation of potassium carbonate and potassium hydrogencarbonate results in the formation of potassium and carbonate ions. Potassium and carbonate ions are naturally occurring, effectively processed and regulated essential compounds in the body. K⁺or CO₃^2-resulting from the ionisation (dissociation) of K₂CO₃will not influence the natural K⁺or CO₃^2-level in the body due to the natural regulation mechanisms. Absence of intrinsic toxic properties of potassium hydrogencarbonate as well as of potassium carbonate are taken for granted, which is affirmed by their long-standing safe use in food and pharmaceuticals with no limitations other than current good manufacturing practice and their GRAS (generally recognized as safe) status in the USA.

Justification for read across

Potassium carbonate as well as potassium hydrogencarbonate rapidly dissociates in biological fluids to yield carbonate ions (CO₃^2- and HCO₃^-) and potassium (K⁺) ions. Therefore, the systemic action of potassium carbonate and potassium hydrogencarbonate must be discussed for their constituents carbonate ions and potassium ions separately. All ions involved, are naturally occurring essential ions in human beings. Their metabolism and mechanisms of action are well reviewed in standard textbooks on pharmacology and physiology. The carbonate and potassium ions coming from potassium carbonate and potassium hydrogencarbonate are incorporated into, processed and regulated by the same physiological processes independently of their individual source (for further details see chapter 7.1). Thus, once dissociated, the physiological activity of potassium carbonate and potassium hydrogencarbonate is expected to be identical and therefore, data on the systemic activity of potassium carbonate can be likewise used for potassium hydrogencarbonate and vice versa.

Also substances with a potassium or a carbonate moiety and nontoxic counterions can be taken into consideration to assess the intrinsic systemic activities of the two moieties carbonate and potassium of potassium carbonate and potassium hydrogencarbonate as well. Because, once dissociated, the individual source of the carbonate and potassium ions is not longer relevant for their activity in the body and e.g. a potassium ion dissociated from potassium chloride will be indiscernible from a potassium ion dissociated from potassium carbonate or potassium hydrogencarbonate.

A detailed justification for read-across is attached to iuclid section 13.