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Description of key information

No studies on oral repeated dose toxicity of potassium carbonate are available. Reliable studies on oral repeated dose toxicity on closely related read-across substance potassium hydrogencarbonate are available. These studies included 4-week, 13-week, 18-month, and 30-month studies, in which rats were treated with very high doses of potassium hydrogen carbonate in their feed (2 and 4%). The studies were not performed according to an explicitly mentioned international guideline, but accomplishment and documentation cover a broad range of the requirements of the usual guidelines for repeated dose toxicity studies. Thus, the studies are relevant, reliable and adequate for the purpose of assessing repeated dose toxicity. 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.
The NOAELs of potassium hydrogencarbonate relevant to humans is the highest dose tested of 4 % in diet, based on body weight and diet intake corresponding to 
- 6054 mg/kg bw/d (43.8 mmol/kg bw/d) in males and 6137 mg/kg bw/d (44.4 mmol/kg bw/d) in females in the 4-week-study
- 4326 mg/kg bw/d (31.3 mmol/kg bw/d) in males and 4879 mg/kg bw/d (35.3 mmol/kg bw/d) in females in the 13-week-study
- 2861 mg/kg bw/d (20.7 mmol/kg bw/d) in males and 3566 mg/kg bw/d (25.8 mmol/kg bw/d) in females in the 18-month study and of 
- 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 in the 30-month study
The molecular weights of potassium hydrogencarbonate (KHCO3) and  potassium carbonate (K2CO3) are 100,12 g and 138, 20 g., respectively.
Therefore, with respect to the carbonate moiety, 1000 mg potassium hydrogencarbonate are equivalent to 1380 mg potassium carbonate, and with respect to the potassium moiety, 1000 mg potassium hydrogencarbonate are equivalent to 690 mg potassium carbonate.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: 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:
reference to same study
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 13-week-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% or 4%, acid forming diet), or potassium chloride (3%, neutral diet providing K+ and Cl- in amounts equimolar to those in the 4% potassium hydrogencarbonate diet and the 2.1% ammonium chloride diet, respectively).
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Dose / conc.:
2 other: % in diet
Dose / conc.:
4 other: % in diet
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Study groups:
- control group: unsupplemented institutes cereal based rodent diet
- 2% potassium hydrogencarbonate in diet (approximately 2046 mg/kg bw/d for males and 2294 mg/kg bw/d for females)
- 4% potassium hydrogencarbonate in diet (approximately 4326 mg/kg bw/d for males and 4879 mg/kg bw/d for females)
- Satellite groups: 2.1% and 4% NH4Cl (acid-forming diets) and neutral diet supplemented with 3% KCl providing K+ and Cl- in amounts equimolar to those in the 4% KHCO3 diet and the 2.1% NH4Cl diet, respectively
Post-exposure period: none
Clinical signs:
no effects observed
Description (incidence and severity):
- 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
Mortality:
no mortality observed
Description (incidence):
- Mortality and time of death: no animal died
Body weight and weight changes:
no effects observed
Description (incidence and severity):
- no treatment-related effects
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
- Food consumption: no treatment-related effects
- ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX:
-- males: 2046 and 4326 mg/kg bw/d (14.8 and 31.3 mmol/kg bw/d)
-- females: 2294 and 4879 mg/kg bw/d (16.6 and 35.3 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:
effects observed, treatment-related
Description (incidence and severity):
- Blood gas analysis: dose-related increase in base excess, associated with higher blood pH and bicarbonate concentrations
- Clinical biochemistry: potassium levels in plasma were generally increased in males and females fed 2 or 4% potassium hydrogencarbonate, although the differences with the controls were not always statistically significant; significant base excess in both sexes of both dose groups; no treatment-related effects on further measured blood clinical biochemistry parameters
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; 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; 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
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
- Kidney weights: relative kidney weights in females of the high dose group significantly increased and in males of this group tendentiously but not statistically significant increased
- Further examined organ weights: there were no consistent or treatment-related changes in the weights of adrenals, brain, testes, liver, spleen, ovaries, pituitary, thyroid, thymus or heart
Gross pathological findings:
no effects observed
Description (incidence and severity):
- macroscopic examination at necropsy did not reveal 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 the high dose group, the zona glomerosa was distinctly wider than in controls, the cells in this area were enlarged and showed a finely vacuolar cytoplasm (10 animals per sex examined, findings in 9/10 males (significant, control: 1/10) and 4/10 females (not significant, control: 0/10). 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 the high dose group, oncocytic tubules but no severe or very severe nephrosis or urothelial hyperplasia in the pelvis (10 animals per sex examined, findings in 10/10 males (significant, control: 0/10) and 9/10 females (significant, control: 0/10). 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: no treatment-related significant effects; examination of the urinary bladder showed (not significant) very slight to slight simple epithelial hyperplasia in 4/10 and 3/10 males (control: 0/10) and 1/10 and 1/10 females (control: 0/10) in the low and the high dose groups, respectively.
- Reproductive organs: no treatment-related effects (epididymides, testes, ovaries, and uterus examined)
- Further examined organs and tissues: no treatment-related effects
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
- Calcium content in femur: no treatment-related effects
Dose descriptor:
NOAEL
Effect level:
4 326 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Highest dose tested (4% in diet); no adverse effects relevant to humans observed; only adaptive effects on very high ion ingestion seen.
Dose descriptor:
NOAEL
Effect level:
4 879 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Highest dose tested (4% in diet); no adverse effects relevant to humans observed; only adaptive effects on very high ion ingestion seen.
Critical effects observed:
no
Conclusions:
The NOAELs of potassium hydrogencarbonate relevant to humans is the highest dose tested of 4 % in diet, based on body weight and diet intake correspond to 4326 mg/kg bw/d (31.3 mmol/kg bw/d) in males and 4879 mg/kg bw/d (35.3 mmol/kg bw/d) in females in the 13-week-study
The molecular weights of potassium hydrogencarbonate (KHCO3) and potassium carbonate (K2CO3) are 100.12 g/mol and 138. 20 g/mol, respectively.
Therefore, with respect to the carbonate moiety, 1000 mg potassium hydrogencarbonate are equivalent to 1380 mg potassium carbonate, and with respect to the potassium moiety, 1000 mg potassium hydrogencarbonate are equivalent to 690 mg potassium carbonate.
Endpoint:
chronic toxicity: 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:
reference to same study
Reason / purpose for cross-reference:
read-across source
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
78 weeks (18 months)
Frequency of treatment:
daily
Dose / conc.:
2 other: % in diet
Dose / conc.:
4 other: % in diet
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Other examinations:
no
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
Mortality:
no mortality observed
Description (incidence):
- Mortality and time of death: mortality rate was not affected
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
- mean body weights decreased in males of the high dose group (decrease in the range of 4 to 10%, no exact data given)
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
- Food consumption: no treatment-related effects
- ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX:
-- males: 1299 and 2861 mg/kg bw/d (9.4 and 20.7 mmol/kg bw/d)
-- females: 1686 and 3566 mg/kg bw/d (12.2 and 25.8 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:
effects observed, treatment-related
Description (incidence and severity):
- Blood gas analysis: dose-related increase in base excess, associated with higher blood pH and bicarbonate concentrations
- Clinical biochemistry:potassium levels in plasma were generally increased in males and females fed 2 or 4% potassium hydrogencarbonate, although the differences with the controls were not always statistically significant; significant base excess in both sexes of both dose groups; no treatment-related effects on further measured blood clinical biochemistry parameters
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
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
- Kidney weights: relative kidney weights in both sexes of both dose groups tendentiously but except of low dose female group not statistically significant increased
- 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: some animals showed thickening and/or induration of the urinary bladder wall, irregular serosal surface and/or luminal dilatation; on male of the 4% group was found to have a grossly visible bladder mass, which extended into the dorsal prostate; 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 the high dose group, the zona glomerosa was distinctly wider than in controls, the cells in this area were enlarged and showed a finely vacuolar cytoplasm (13-15 animals per sex and dose examined (both survivors and intercurrent deaths), findings in the low and high dose group in 3 (not significant) and 10 males (significant, control: 0), respectively, and 2 (not significant) and 9 females (significant, control: 0), 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 (13-15 animals per sex and dose examined (both survivors and intercurrent deaths), findings in the low and high dose group in 4 (significant) and 15 males (significant, control: 0), respectively, and 5 (significant) and 13 females (significant, control: 0), 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 incidences of simple epithelial hyperplasia, of papillary hyperplasia and nodular hyperplasia were increased. However significantly and dose depended increases were limited to simple epithelial hyperplasie in both males and females of the low and the high dose group and papillary epithelial hyperplasia, nodular epithelial hyperplasia and transitional-cell papilloma (one or multiple) in the high dose females.
--Simple epithelial hyperplasia in 0/15, 5/13 (significant) and 6/15 (significant) males, and 1/15, 5/15 (not significant) and 9/15 (significant) females in the control, the low- and the high-dose group, respectively
-- Papillary epithelial hyperplasia in 0/15, 4/13 (significant) and 1/15 (not significant) males, and 0/15, 1/15 (not significant) and 5/15 (significant) females in the control, the low- and the high-dose group, respectively
-- Nodular epithelial hyperplasia in 0/15, 2/13 (not significant) and 0/15 (not significant) males, and 0/15, 1/15 (not significant) and 4/15 (not 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 0/15, 0/13 (not significant) and 0/15 (not significant) males, and 0/15, 0/15 (not significant) and 2/15 (not significant) females in the control, the low- and the high-dose group, respectively
-- Transitional-cell carcinoma in 0/15, 0/13 (not significant) and 1/15 (not significant) males, and 0/15, 0/15 (not significant) and 2/15 (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:
2 861 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
3 566 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
no
Conclusions:
The NOAELs of potassium hydrogencarbonate relevant to humans is the highest dose tested of 4 % in diet, based on body weight and diet intake correspond to 2861 mg/kg bw/d (20.7 mmol/kg bw/d) in males and 3566 mg/kg bw/d (25.8 mmol/kg bw/d) in females in the 18-month study
The molecular weights of potassium hydrogencarbonate (KHCO3) and potassium carbonate (K2CO3) are 100.12 g/mol and 138. 20 g/mol, respectively.
Therefore, with respect to the carbonate moiety, 1000 mg potassium hydrogencarbonate are equivalent to 1380 mg potassium carbonate, and with respect to the potassium moiety, 1000 mg potassium hydrogencarbonate are equivalent to 690 mg potassium carbonate.
Endpoint:
chronic toxicity: oral
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 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:
reference to same study
Reason / purpose for cross-reference:
read-across source
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
130 weeks (30 months)
Frequency of treatment:
daily
Dose / conc.:
2 other: % in diet
Dose / conc.:
4 other: % in diet
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Other examinations:
no
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
Mortality:
no mortality observed
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):
no effects observed
Description (incidence and severity):
- Food consumption: no treatment-related effects
- 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:
The NOAELs of potassium hydrogencarbonate relevant to humans is the highest dose tested of 4 % in diet, based on body weight and diet intake correspond 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 in the 30-month study
The molecular weights of potassium hydrogencarbonate (KHCO3) and potassium carbonate (K2CO3) are 100.12 g/mol and 138. 20 g/mol, respectively.
Therefore, with respect to the carbonate moiety, 1000 mg potassium hydrogencarbonate are equivalent to 1380 mg potassium carbonate, and with respect to the potassium moiety, 1000 mg potassium hydrogencarbonate are equivalent to 690 mg potassium carbonate.
Endpoint:
short-term repeated dose toxicity: 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:
reference to same study
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
daily
Dose / conc.:
2 other: % in diet
Dose / conc.:
4 other: % in diet
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Other examinations:
no
Clinical signs:
no effects observed
Description (incidence and severity):
no treatment-related abnormalities in condition or behaviour
Mortality:
no mortality observed
Description (incidence):
Mortality and time of death: no animal died
Body weight and weight changes:
no effects observed
Description (incidence and severity):
- no treatment-related effects
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
- Food consumption: no treatment-related effects
- ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX:
-- males: 2944 and 6054 mg/kg bw/d (21.3 and 43.8 mmol/kg bw/d)
-- females: 2902 and 6137 mg/kg bw/d (21.0 and 44.4 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:
effects observed, treatment-related
Description (incidence and severity):
- Blood gas analysis: dose-related increase in base excess, associated with higher blood pH and bicarbonate concentrations
- Clinical biochemistry: potassium levels in plasma were generally increased in males and females fed 2 or 4% potassium hydrogencarbonate, although the differences with the controls were not always statistically significant; significant base excess in both sexes of both dose groups; no treatment-related effects on further measured blood clinical biochemistry parameters
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
- Urine parameter of non-fasted animals: not performed
- Urinary pH and acid indices: pH increased in both dose groups (pH values: 8.5 to 8.8 (control: 7.6 to 7.7)), 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; 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
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
- Kidney weight: relative kidney weights in both sexes of both dose groups tendentiously but not statistically significant increased
- Further examined organ weights: there were no consistent or treatment-related changes in the weights of adrenals, brain, testes, liver, spleen, ovaries, pituitary, thyroid, thymus or heart
Gross pathological findings:
no effects observed
Description (incidence and severity):
- macroscopic examination at necropsy did not reveal significant differences among the treatment groups and the controls
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
- no significant differences among the groups treated with potassium hydrogencarbonate and the controls; no treatment-related significant effects
- examination of the urinary bladder showed (not significant) very slight to slight simple epithelial hyperplasia in 1/10 and 2/10 males (control: 0/10) and 1/10 and 3/10 females (control: 0/10) in the low and the high dose groups, respectively
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
- Calcium content in femur: no treatment-related effects
Dose descriptor:
NOAEL
Effect level:
6 054 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Highest dose tested (4 % in diet); no adverse effects relevant to humans observed; only adaptive effects on very high ion ingestion seen.
Dose descriptor:
NOAEL
Effect level:
6 137 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Highest dose tested (4 % in diet); no adverse effects relevant to humans observed; only adaptive effects on very high ion ingestion seen.
Critical effects observed:
no
Conclusions:
The NOAELs of potassium hydrogencarbonate relevant to humans is the highest dose tested of 4 % in diet, based on body weight and diet intake correspond to 6054 mg/kg bw/d (43.8 mmol/kg bw/d) in males and 6137 mg/kg bw/d (44.4 mmol/kg bw/d) in females in the 4-week-study

The molecular weights of potassium hydrogencarbonate (KHCO3) and potassium carbonate (K2CO3) are 100.12 g/mol and 138. 20 g/mol, respectively.
Therefore, with respect to the carbonate moiety, 1000 mg potassium hydrogencarbonate are equivalent to 1380 mg potassium carbonate, and with respect to the potassium moiety, 1000 mg potassium hydrogencarbonate are equivalent to 690 mg potassium carbonate.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
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
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD Guideline 424 (Neurotoxicity Study in Rodents)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI, USA (Sprague-Dawley Crl:CD VAF/plus)
- Age at study initiation: approximately 43 days
- Weight at arrival at study laboratory:  Males: 130 g, Females: 110 g
- Fasting period before study:
- Housing: All animals were individually housed in stainless-steel, wire-mesh cages suspended above cage papers
- Diet: Purina certified rodent chow 5002, ad libitum during nonexposure periods
- Water: tap water, ad libitum during nonexposure periods
- Acclimation period: 10 to 13 days

ENVIRONMENTAL CONDITIONS
- Temperature: 23 +/- 2 °C
- Humidity: 40 - 70 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 13 h light/11 h dark cycle

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: The aerosol concentration was reduced to the target concentrations by dilution with the chamber ventilation air flow.
Remarks on MMAD:
MMAD / GSD: Respirable aerosol was generated, similar in all exposure groups (mean MMAD of all samples ranged from 2.16 to 2.54 µm)
Aerosol particle size was determined twice during each exposure week for each test article exposure chamber using an INTOX Products, Inc. (Albuquerque, NM), model 02-140/JB seven-stage cascade impactor with cutoff diameters ranging from 0.26 to 5.27 µm.
Details on inhalation exposure:
All animals were caged individually and exposed, 6 h/d for 21 consecutive days, in stainless-steel and glass whole-body inhalation chambers operated under dynamic conditions of at least 12 air changes per hour. Respirable-range aerosols were generated with stainless-steel atomizers (Spraying Systems, Inc., Wheaton, lL) fitted with a no. 1650 fluid nozzle and a no. 64 air eap. The atomizer sprayed into a 6-L glass chamber to collect large droplets produced during the atomization process. The resulting aerosol was piped to the exposure chamber inlets, where the aerosol concentration was reduced to the target concentrations of 0.1, 0.2, or 0.4 mg/L by dilution with the chamber ventilation air flow.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Target concentrations (mg/L): control (filtered air), 0.1, 0.2, 0.4; Mean actual concentrations (mg/L): control, 0.11, 0.16, 0.41
The actual exposure concentrations were determined by standard gravimetric methods after collecting samples on 25-mm Teflon filters (Millipore type FG, 0.2 µm).
Test atmosphere homogeneity was determined prior to Initiation of animal exposure for each target exposure level. Analytical confirmation of exposure concentrations was performed by ion-exchange chromatography using electrochemical conductivity detection for potassium.
Duration of treatment / exposure:
21 days
Frequency of treatment:
daily, 6 hours per day
Remarks:
Doses / Concentrations:
0.1, 0.2 and 0.4 mg used scrubbing solution/L
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0.11, 0.16 and 0.41 mg used scrubbing solution/L
Basis:
analytical conc.
No. of animals per sex per dose:
15 rats per sex per dose level were assigned to the systemic toxicity study part and 15 rats per sex per dose level were assigned to the neurotoxicity study part
Control animals:
yes, sham-exposed
Details on study design:

- Dose selection rationale: In a 2-week dose range finding study systemic toxicity (weight loss and respiratory symptoms) were noted at 0.5 mg/L.

- Rationale for selecting satellite groups: not given.

- Post-exposure recovery period in satellite groups: 14 days, 5 rats per sex per dose level in each study part
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality, abnormal behavior and appearance was observed twice daily throughout the study.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
Clinical observations during the exposure period: daily, prior to placement into the inhalation chambers, during the 6-h daily exposure period, and approximately 1 h following the completion of the daily exposure.

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly, beginning 1 week prior to treatment

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined: twice weekly, beginning 1 week prior to treatment
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the first exposure, during the treatment period (day 18), and after completion of exposure, all ocular examinations were conducted using a biomicroscope and indirect ophthalmoscope, preceded by mydriasis (1% atropine sulfate solution).
- Dose groups that were examined: all animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the primary (day 21) and satellite necropsies (day 35)
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes overnight
- How many animals: all surviving animals per group and sex
- Parameters checked:
erythrocyte, leukocyte, differential leukocyte, and platelet counts, hemoglobin concentration, hematocrit, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, prothrombin time, and activated partial thromboplastin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the primary (day 21) and satellite necropsies (day 35)
- Animals fasted: Yes overnight
- How many animals: all surviving animals per group and sex
- Parameters checked:
creatine kinase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, lactate dehydrogenase, and alkaline phosphatase activities, concentrations of blood urea nitrogen, total serum protein, albumin, globulin, creatinine, cholesterol, glucose, calcium, phosphorus, sodium, potassium, chloride, and total bilirubin

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- A functional observational battery (FOB) was conducted on 10 rats per sex per group at prestudy, 1 h following the completion of the first exposure (day 0), approximately 18 h after the first exposure (Day 1), following completion of the last exposure (day 21), and on 5 rats per sex per group at the end of the recovery period (day 35). Tests included, while in the home cage, each animal was observed and scored for posture, convulsions/tremors, biting, circling, writhing, palpebral closure, and vocalization; upon removal from the cage: ease of removal, ease of handling, lacrimation, chromodacryorrhea, piloerection, palpebral closure, fur appearance, and salivation; open-field observations over a 2-min period: time to first steps, degree of locomotion, arousal, convulsions/tremors, grooming, gait abnormalities, responses to approach, startle, touch, and tail pinch, olfactory orientation, air righting reflex, forelimb and hindlimb extension, and eye-blink response; grip strength, hind-limb extensor strength, hind-limb food splay, rotarod performance, body temperature, and catalepsy were also monitored and recorded.

- Locomotor activity was recorded after completion of each FOB session using a Digiscan "Micro" animal activity system; sessions were 40 min in length, and each session was divided into for 10-min intervals.

- Neurohistopathologic examinations: Brain weight and dimension were recorded and neurohistopathologic examinations were conducted on various sections of the brain (forbrain, center of cerebrum, midbrain, cerebellum and pons, and medulla), spinal cord (cross and longitudinal sections of the cervical and lumbar cord), eyes, and nerves (optic, sciatic, neural, tibia, and peroneal).


Sacrifice and pathology:
A complete necropsy was conducted on all animals that were found dead or euthanized at the scheduled primary (day 21) and satellite sacrifice (day 35, after 21 exposure and 14 recovery days).

GROSS PATHOLOGY: Yes
The necropsy included an examination of external surface, all orifices, and the cranial, thoracic, abdominal, and pelvic cavities, including the viscera. The adrenals, brain, heart, kidneys, liver, lungs (prior to inflation with fixative), ovaries, spleen, testes, and thymus were removed and weighed. Aorta, bone marrow (sternal and femoral), exorbital lacrimal glands, eyes, femur, gastrointestinal tract, mesenteric lymph nodes, mammary glands, nasal cavities, optic nerve, pancreas, sciatic nerve, pituitary, prostate, salivary glands, seminal vesicles, thyroid, trachea, urinary bladder, uterus, vagina, and all gross lesions were also removed.
All Tissues including the entire head (after removal of other appropriate specified tissue) were placed in 10% neutral buffered formalin. Following fixation, the sculls were decalcified until soft. All tissues were stained with hematoxilin and eosin.

HISTOPATHOLOGY: Yes
Microscopic evaluation was conducted on all tissues for the control and highest exposure level groups. Microscopic examination of the nasal cavities, lungs, liver, kidneys, and gross lesions was performed for the low and mid exposure level groups. Levels I and II of the nasal cavities and the lungs were examined microscopically from all animals at the satellite necropsy.
Statistics:
Body weights, body weight changes, food consumption, clinical pathology parameters, and organ weights were analyzed by a one-way analysis of variance (ANOVA). Pair wise comparisons between test and control groups were made with Dunnett´s test. Continuous FOB and motor activity data were analyzed using a two-way repeated measure ANOVA. If significant treatment or treatment-time interactions occurred, a one-way ANOVA was conducted at each time point. When corresponding F-test for difference was significant, Dunnett´s multiple test was conducted to determine significant differences from the control group (p < .05). Non-continuous data were analyzed with Fischer´s exact test using the .05 significance level.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
- Clinical observations during the exposure period: no treatment-related abnormalities
- Abnormal behavior and appearance: no treatment-related abnormalities
Mortality:
mortality observed, treatment-related
Description (incidence):
One female in the 0.4 mg/l exposure level died on day 14 of exposure. Gasping was noted prior to death, but the specific cause of death could not be identified at necropsy.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
-- 0.1 and 0.2 mg/l dose groups: no treatment-related abnormalities
-- 0.4 mg/l dose group: in females no treatment-related abnormalities; in males, a statistically significant reduction in weight gain of 6 g was noted during study days 10 to 14 in conjunction with a statistically significant reduction in food intake of 2 g. During the recovery period the mean body weight gain of the high-exposure males was comparable to control values.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
-- 0.4 mg/l dose group: in females no treatment-related abnormalities; in males, a statistically significant reduction in weight gain of 6 g was noted during study days 10 to 14 in conjunction with a statistically significant reduction in food intake of 2 g
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
no treatment-related effects
In the 0.2 mg/L group females, the mean albumin-globulin ratio was statistically higher than control values at d 21; this was not observed at higher exposure levels and thus was not attributed to exposure.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
- Functional observational battery (FOB): No apparent test-material-related differences; no treatment-related effects were noted in the home cage observations, open-field, sensory, neuromuscular, and physiological observations and locomotor activities at any exposure level. The rotarod performance activities in the 0.2 mg/L males were decreased. However, rotarod performance activities were not changed in the 0.2 mg/L females or 0.4 mg/L groups.
- Brain weight and size: no treatment-related effects.
- Neurohistopathologic examinations: no treatment-related findings;
No unusual microscopic lesions were observed in any of the central or peripheral nervous system tissues examined. Digestion chambers were noted in the peroneal nerve of one control female and one 0.4 mg/l male, and in the sciatic nerve of one control male.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
- Mean absolute and relative lung weights at end of exposure period: significantly dose-related increased (9-35%) in both male and females in all treated groups
- Mean absolute and relative lung weights at end of recovery period: comparable to control values except for a significant increase in the 0.4 mg/l group females
- Further measured organ weights: no treatment-related effects.
In the female 0.2 mg/L satellite recovery group, a significant increase in absolute thymus gland weight was noted. However, this change was not attributed to treatment since a dose-response relationship was not observed at higher exposure levels.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
-- Respiratory tract at end of exposure period: Effects attributed to the irritant property of the test material were seen in all dose levels.
--- Nasal cavity: In level I of the nasal cavities, minimal to moderate epithelial hyperplasia and minimal to moderate epithelial necrosis were found in all treated groups.
In level II of the nasal cavities, mild cytoplasmic vacuolization of the olfactory epithelium lining dorsal meatus was noted in the 0.2 and 0.4 mg/L groups. Minimal epithelial necrosis in level II of nasal cavities was found in two 0.4 mg/l group females.

--- Lungs: Bronchiolization was observed in the treated groups, and alveolar macrophage infiltration was found in both control and treated groups. These changes were mostly multifocal and accompanied by minimal to moderate nonsuppurative interstitial inflammation in a single 0.2 mg/L male, and 7 males and 4 females in the 0.4 mg/L group

-- Respiratory tract at end of recovery period
--- Nasal cavity: There were no test-material-related findings observed in either level I or II of the nasal cavities, thus demonstrating reversibility of effects seen in the nasal cavity at the end of exposure period.
--- Lungs: Mild bronchiolization and alveolar macrophage infiltration were found in the high-exposure group. A general trend toward reversibility of the changes in the lungs was discerned due to the decreased incidence of alveolar macrophage infiltration, nonsuppurative interstitial inflammation, and severity of the effects seen in this dose-group. The absence of bronchiolization in the low- and mid-dose groups was also considered as evidence of reversibility.

-- Reproductive organs: no treatment-related findings (ovaries, mammary glands, uterus, vagina, testes, prostate, and seminal vesicles examined)
-- Further examined organs and tissues: no treatment-related findings
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOEC
Remarks:
systemic
Effect level:
0.4 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: highest concentration tested, no effects, based on product
Dose descriptor:
NOEC
Remarks:
systemic
Effect level:
0.123 mg/L air
Sex:
male/female
Basis for effect level:
other: recalculated, based on potassium carbonate content of test item
Dose descriptor:
NOAEC
Remarks:
local
Effect level:
0.2 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEC
Remarks:
local
Effect level:
0.062 mg/L air
Sex:
male/female
Basis for effect level:
other: recalculated, based on potassium carbonate content of test item
Dose descriptor:
LOEC
Remarks:
local
Effect level:
0.1 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
LOEC
Remarks:
local
Effect level:
0.031 mg/L air
Sex:
male/female
Basis for effect level:
other: recalculated, based on potassium carbonate content of test item
Dose descriptor:
NOEC
Remarks:
neurotoxicity
Effect level:
0.4 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: highest concentration tested; no effects (FOB, locomotor activities, brain weight and size, neurohistopathology), based on product
Dose descriptor:
NOEC
Remarks:
neurotoxicity
Effect level:
0.123 mg/L air
Sex:
male/female
Basis for effect level:
other: recalculated, based on potassium carbonate content of test item
Critical effects observed:
no
Conclusions:
Whole body exposure to up to and including 0.4 mg/l of a used scrubbing solution aerosol (pH 9.9, with main active ingredient 30.8% potassium carbonate) 6 h/d for 21 consecutive days did not result in any relevant systemic toxicity or neurotoxicity in either male or female rats. Reversible histopathological changes were noted in levels I and II of the nasal cavities and in the lungs of the treated animals, and were indicative of a local response to the irritant property of the test solution.The respiratory-tract findings were considered a local response to the high alkalinity of the test material as substantiated by the return to normal upon cessation of exposure.
Executive summary:

In a sub-acute inhalation toxicity study similar to OECD guideline 412 (Repeated Dose Inhalation Toxicity: 28/14-Day) and OECD Guideline 424 (Neurotoxicity Study in Rodents) an aerosol of a used potassium carbonate-based scrubbing solution “Catacarb” (pH 9.9, with main active ingredient 30.8% potassium carbonate; further ingredients: 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) was administered to groups of 30 Sprague Dawley rats per sex and concentration The scrubbing solution was administered by whole body exposure at concentrations of 0, 0.1, 0.2 and 0.4 mg/L for 6 hours per day, 7 days/week for a total of 21 consecutive days. A functional observational battery (FOB) and locomotor activity tests were conducted on 10 rats per sex per group at prestudy, 1 h following the completion of the first exposure (d 0), approximately 18 h after the first exposure (d 1), following completion of the last exposure (d 21), and on 5 rats per sex per group at the end of the recovery period (d 35).At the end of the exposure period, 10 rats per sex per dose level were anesthetized with methoxyfluorane, exsanguinated, and necropsied for systemic toxicity evaluation and 10 rats per sex per dose level were euthanized by carbon dioxide and then perfused in situ for neurotoxic evaluation. The remaining 10 rats per sex per dose level were allowed a 14-d recovery period, and sacrificed on study day 35, 5 rats each were evaluated for systemic toxicity or neurotoxicity.

One female in the 0.4 mg/l exposure level died on day 14 of exposure. Gasping was noted prior to death, but the specific cause of death could not be identified at necropsy. Food consumption and weight gain were not affected in the 0.1 and 0.2 mg/L group males and females and 0.4 mg/L group females. In the 0.4 mg/L males, a statistically significant reduction in weight gain of 6 g was noted during study days 10-14 in conjunction with a statistically significant reduction in food intake of 2 g. During the recovery period the mean body weight gain of the high-exposure males was comparable to control values. No apparent adverse effects were noted at any exposure level as determined by clinical observations, hematology, serum chemistry, ophthalmologic observations, and gross pathology. Statistically significant increases in lung weights were noted at all treatment levels but returned to control values upon cessation of exposure except for the 0.4 mg/L female group. There were no significant changes in other organ weights. Histopathological findings were restricted to the respiratory tract and characterized by minimal to moderate epithelial hyperplasia, epithelial necrosis, and cytoplasmic vacuolation at levels I and II of the nasal cavities. Lung bronchiolization and alveolar macrophage infiltration were also observed. The histopathological respiratory tract findings were fully reversible in all dose groups, except for the 0.4 mg/l exposure group, in which bronchiolization and alveolar macrophage infiltration were tendentially but not fully reversible. The respiratory-tract findings were considered a local response to the high alkalinity of the test material (pH approximately 9.9) as substantiated by the return to normal upon cessation of exposure. No treatment-related findings were seen in further examined organs and tissues including the reproductive organs (ovaries, mammary glands, uterus, vagina, testes, prostate, and seminal vesicles examined). Exposure to scrubbing solution had no adverse effect on FOB endpoints and locomotor activity evaluations, brain weight and size, and neurohistopathologic examinations.

The study authors came to the conclusion, that whole body exposure to up to and including 0.4 mg/l of a used scrubbing solution aerosol (pH 9.9, with main active ingredient 30.8% potassium carbonate) 6 h/d for 21 consecutive days did not result in any persistent systemic toxicity or neurotoxicity in either male or female rats. Reversible histopathological changes were noted in levels I and II of the nasal cavities and in the lungs of the treated animals, and were indicative of a local response to the irritant property of the test solution.The respiratory-tract findings were considered a local response to the distinct alkalinity of the test material as substantiated by the return to normal upon cessation of exposure.

NOEC systemic based on product 0.4.mg/l air

NOAEC based on potassium carbonate content of test item: 0.123 mg/l air

 

NOAEC local based on product: 0.2 mg/l air

NOAEC based on potassium carbonate content of test item: 0.062 mg/l air

NOAEC local derivation based on temporary histopathological respiratory tract findings and increased lung weights considered as a local response to the high alkalinity of the test material in all dose groups (0.1, 0.2 and 0.4 mg scrubbing solution/l), fully reversible within 14 days up to and including the dose level of 0.2 mg/l, tendentially reversible at dose level 0.4 mg/l (LOEC is 0.1 mg/l (lowest tested concentration))

Toxicodynamic cause of the irritating effect: solely alkalinity

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Repeated dose toxicity: oral

Wistar rats were maintained on diets containing 2 or 4% of the closely related read-across substance potassium hydrogencarbonate over 4-weeks, 13-weeks, 18-months, and 30-months (Lina 2004, Lina and Kuijpers 2004, Lina, Hollanders and Kuijpers 1994). A justification for read-across is attached to Iuclid section 13.

Object of the studies was to examine the effects of died-induced acid-base disturbances. The studies were not performed according to an explicitly mentioned international guideline, but accomplishment and documentation cover a broad range of the requirements of the usual guidelines for repeated dose toxicity studies. Thus, the studies are relevant, reliable and adequate for the purpose of assessing repeated dose toxicity. Even though the rats were treated with very high doses of potassium hydrogencarbonate in their feed, in the highest dose groups corresponding to daily intakes of more than or nearly 3000 mg/kg bw in the 18- and 30-month studies to even more than 6000 mg/kg bw in the 4-week study, and in the lowest dose groups of still distinctly more than the guideline limit dose of repeated dose toxicity studies (1000 mg/kg bw) in the 30-month study to approximately 2900 mg/kg bw in the 4-week study, only few and mainly adaptive responses to the treatment were seen. Animals which received 18 months or longer 4% potassium hydrogencarbonate in their feed showed a slightly impaired body weight. In the blood, increased potassium levels and base excess, associated with higher blood pH and bicarbonate concentrations were seen. The water intake was increased up to 40% and also the urinary volume, potassium excretion and pH were distinctly increased, the urinary net acid excretion was decreased. The microscopic alterations seen in the adrenals and the kidneys may be interpreted as adaptive response to chronic simulation of the adrenal cortex by potassium cations and as a functional adaptation in order to compensate the increased work load of the kidneys, respectively and regarded as of no toxicological relevance. The (missing) relevance to humans of preneoplastic and neoplastic histopathological epitelial alterations in the urinary bladder are discussed in Chapter 5.8 Carcinogenicity. Thus, up to and including the highest dose tested of 4 % potassium hydrogencarbonate in the diet administered for 4 weeks, 13 weeks, 18 months or almost a lifetime (30 months), the rats adapted relatively easily to the feeding of these very high dose levels far exceeding the guideline limit dose of repeated dose toxicity studies and were free of treatment related adverse effects relevant to humans.

The NOAELs of potassium hydrogencarbonate relevant to humans is the highest dose tested of 4 % in diet, based on body weight and diet intake correspond to

- 6054 mg/kg bw/d (43.8 mmol/kg bw/d) in males and 6137 mg/kg bw/d (44.4 mmol/kg bw/d) in females in the 4-week-study

- 4326 mg/kg bw/d (31.3 mmol/kg bw/d) in males and 4879 mg/kg bw/d (35.3 mmol/kg bw/d) in females in the 13-week-study

- 2861 mg/kg bw/d (20.7 mmol/kg bw/d) in males and 3566 mg/kg bw/d (25.8 mmol/kg bw/d) in females in the 18-month study and of

- 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 in the 30-month study

The molecular weights of potassium hydrogencarbonate (KHCO3) and potassium carbonate (K2CO3) are 100.12 g/mol and 138. 20 g/mol, respectively.

Therefore, with respect to the carbonate moiety, 1000 mg potassium hydrogencarbonate are equivalent to 1380 mg potassium carbonate, and with respect to the potassium moiety, 1000 mg potassium hydrogencarbonate are equivalent to 690 mg potassium carbonate.

Based on these study results, the approved use of potassium hydrogencarbonate as well as 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 systemically non-toxic. Thus, there is no need to set DNELs for systemic repeated dose toxicity.

Repeated dose toxicity: inhalation

In a sub-acute inhalation toxicity study similar to OECD guideline 412 (Repeated Dose Inhalation Toxicity: 28/14-Day) and OECD Guideline 424 (Neurotoxicity Study in Rodents) an aerosol of a used potassium carbonate-based scrubbing solution “Catacarb” was tested. “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).

The scrubbing solution was administered to Sprague Dawley rats by whole body exposure at concentrations of 0, 0.1, 0.2 and 0.4 mg/L for 6 hours per day, 7 days/week for a total of 21 consecutive days. Recovery groups were allowed a 14-d recovery period, and were evaluated for systemic toxicity or neurotoxicity.

No persistent systemic toxicity or neurotoxicity in either male or female rats were observed. Reversible histopathological changes were noted in levels I and II of the nasal cavities and in the lungs of the treated animals, and were indicative of a local response to the irritant property of the test solution. The respiratory-tract findings were considered a local response to the distinct alkalinity of the test material as substantiated by the return to normal upon cessation of exposure.

NOEC systemic based on product 0.4. mg/L air (highest concentration tested)

NOAEC systemic based on potassium carbonate content of test item: 0.123 mg/L air (highest concentration tested)

NOAEC local based on product: 0.2 mg/L air

NOAEC based on potassium carbonate content of test item: 0.062 mg/L air

The NOAEC local derivation is based on temporary histopathological respiratory tract findings and increased lung weights considered as a local irritating response to the distinct alkalinity of the test material in all dose groups (0.1, 0.2 and 0.4 mg scrubbing solution/L), which were fully reversible within 14 days up to and including the dose level of 0.2 mg/L, and tendentially reversible at dose level 0.4 mg/l (LOEC is 0.1 mg/L (lowest tested concentration))

This study is judged as reliable supporting information. However, the study is not judged as suitable for DNEL derivation, since confounding effects of components other than potassium carbonate of the used scrubbing solution can not be excluded. Therefore, this study is not used for DNEL calculation Long-term exposure - local effects inhalation for workers and general population.

Justification for classification or non-classification

There is no evidence for intrinsic toxic properties relevant to humans obtained from the results of reliable and adequate subacute, subchronic and chronic oral studies on rats on the closely related read across substance potassium hydrogencarbonate. The tested dose range far exceeds the guideline limit dose of repeated dose toxicity studies.

Therefore, no classification is required for repeated dose toxicity according to CLP, EU GHS (Regulation (EC) No 1272/2008) with respect to systemic toxicity.