Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
It is concluded that the substance Potassium oxide/Dipotassium oxide does not meet the criteria to be classified for human health hazards for Reproductive toxicity
Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
other: Published data
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
According to OECD 422 and GLP procedures. Alternatively and more conveniently Potassium oxide is synthesized by heating potassium nitrate with metallic potassium: 2 KNO3 + 10 K → 6 K2O + N2 Therefore, the health effects of potassium nitrate need to be considered in the assessment of Potassium oxide
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
not specified
Details on mating procedure:
- Length of cohabitation: 14 days
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Animals on the study were divided between two subgroups (toxicity and reproductive subgroups). The exposure period for males and females in the toxicity subgroup was 28 days. The exposure period for reproductive subgroup males was at most 28 days. The exposure period for reproductive subgroup females was at most 53 days (14 days pre-mating, 14 days mating, and gestational and lactational periods up to lactation day 4).
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 250, 750, and 1,500 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
5 males/group
10 females/group
Control animals:
yes
Details on study design:
- Dose selection rationale: Doses were selected based on parameters assessed in a range-finding study at concentrations up to 1,000 mg/kg/day.
Positive control:
not applicable
Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

gestation length
gestation index
litter size
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in offspring:
number and sex of pups, survival indices, presence of gross anomalies, weight gain
Postmortem examinations (parental animals):
HISTOPATHOLOGY
Histology for reproductive subgroup animals was restricted to retained reproductive organs (and any other abnormalities observed at necropsy).
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Reproductive performance:
no effects observed
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
all animals mated within 4 days
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects at highest dose tested
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Gross pathological findings:
no effects observed
No significant effects were observed on rat’s survival and reproductive organs, or on offspring survival, weight, sex ratio and
congenital defects.
Remarks on result:
other: No significant effects were observed on rat’s survival and reproductive organs, or on offspring survival, weight, sex ratio and congenital defects.
Reproductive effects observed:
not specified

Reproductive subgroup: There were no treatment-related deaths and no signs of overt clinical toxicity. There were no effects on body weight, food consumption, or food efficiency. Mating performance and fertility were unaffected by treatment. All animals mated within 4 days. There were no treatment-related effects on gestation length, gestation index, litter size, offspring survival indices, sex ration, offspring bodyweight, or macropathology for offspring.

Conclusions:
NOAEL: 1,500 mg/kg/day (general toxicity)
1,500 mg/kg/day (reproduction/developmental toxicity)
LOAEL: No adverse effects were seen on general toxicity endpoints. No adverse effects were seen on reproduction/developmental toxicity endpoints.
Alternatively and more conveniently Potassium oxide is synthesized by heating potassium nitrate with metallic potassium:
2 KNO3 + 10 K → 6 K2O + N2
Therefore, the health effects of potassium nitrate need to be considered in the assessment of Potassium oxide
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
other: QSAR Estrogen Receptor Binding method
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
QSAR prediction: Accepted Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Qualifier:
according to
Guideline:
other: QSAR Toolbox Version 3.3.5.17
Principles of method if other than guideline:
This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER binding and possible subsequent endocrine disruption.

The incorporated Toolbox ER binding profiling scheme is based on structural and parametric rules extracted from literature sources and supported by experimental data . The ER-binding profiler clasifies chemicals as non binders or binders depending on molecular weight (MW) and structural characteristics of the chemicals:
1. Very strong binders: Chemicals with MW between 200 and 500 Da and two rings with a hydroxyl group connected to each of them.
2.Strong binders: Chemicals with at least one 5-or 6-members carbon ring with an unhindered hydroxyl or amino group and MW between 200 and 500 Da;
3.Moderate binders: Chemicals with at least one 5-or 6-members carbon ring with an unhindered hydroxyl or amino group and MW between 170 and 200 Da;
4. Weak binders: Chemicals with at least one 5-or 6-members carbon ring with an unhindered hydroxyl or amino group and MW less than 170 Da;

If the target chemical does not meet some of the structural and parametric requirements listed above it is classified as Non binder:
Non binder with impaired hydroxyl or amino group;
Non binder, MW more than 500 Da;
Non binders without hydroxyl or amino group;
Non-binder, non-cyclic.

GLP compliance:
no
Remarks:
not applicable. QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.
Limit test:
no
Species:
other: fish (trout) and mammals.
Strain:
other: QSAR model
Sex:
not specified
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Details on exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Parental animals: Observations and examinations:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
Dipotassium oxide have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Dipotassium oxide does not cause reproductive toxicity.
1.1. CAS number: 12136-45-7
1.2. Chemical name(s):
-potassium oxide (k2o)
-dipotassium oxide
-potash
1.3. Structure codes:
a. SMILES: KO{-}.K{+}
1.4. Profiling results:
-DNA binding by OECD-No alert found
-Est rogen Receptor Binding-Non binder, non cyclic structure
-OECD HPV Chemical Categories-Not categorized
-Protein binding by OECD-No alert
Dose descriptor:
other: Relative ERBA (Estrogen Receptor Binding Affinity)
Effect level:
< -3 other: Log RBA(Relative Binding Affinities )
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: QSAR model (migrated information)
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Dipotassium oxide have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Dipotassium oxide does not cause reproductive toxicity.
1.1. CAS number: 12136-45-7
1.2. Chemical name(s):
-potassium oxide (k2o)
-dipotassium oxide
-potash
1.3. Structure codes:
a. SMILES: KO{-}.K{+}
1.4. Profiling results:
-DNA binding by OECD-No alert found
-Est rogen Receptor Binding-Non binder, non cyclic structure
-OECD HPV Chemical Categories-Not categorized
-Protein binding by OECD-No alert
Dose descriptor:
other: Relative ERBA (Estrogen Receptor Binding Affinity)
Generation:
F1
Effect level:
< -3 other: Log RBA(Relative Binding Affinities )
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
other: Non-ER binder due to non-cyclic molecular structure.Dipotassium oxide have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor
Remarks on result:
other: Generation: QSAR model
Reproductive effects observed:
not specified

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

 

Non-binder, impaired OH or NH2 group

Non-binder without OH or NH2 group

Non-binder, non-cyclic structure

Non-binder, MW > 500

Non-binder, non-cyclic structure– chemicals without cycles and MW =<500

Non-ER binder due to non-cyclic molecular structure.

 

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Popular among these are the “four phase” assessment that includes Comparative Molecular Field Analysis (CoMFA) and the Common Reactivity Pattern Approach (COREPA)

Since the RE-binding is a receptor mediated event, particular organic functional groups, size and shape are critical to binding potency.

Dipotassium oxide have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Dipotassium oxide does not cause reproductive toxicity.

Conclusions:
Non-ER binder due to non-cyclic molecular structure Dipotassium oxide have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Dipotassium oxide does not cause reproductive toxicity.
Executive summary:

Non-ER binder due to non-cyclic molecular structure Dipotassium oxide have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Dipotassium oxide does not cause reproductive toxicity.

1.1. CAS number: 12136-45-7

1.2. Chemical name(s):

-potassium oxide (k2o)

-dipotassium oxide

-potash

1.3. Structure codes:

a. SMILES: KO{-}.K{+}

1.4. Profiling results:

-DNA binding by OECD-No alert found

-Est rogen Receptor Binding-Non binder, non cyclic structure

-OECD HPV Chemical Categories-Not categorized

-Protein binding by OECD-No alert

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
other: Published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
A one generation study with female mice and rats exists for KCl. Doses of 2.35 – 235 mg/kg bw/day in mice and 3.1 – 310 mg/kg bw/day in rats were administered to groups of 21-24 animals by single daily oral intubation. Body weights were recorded during 17 days for mice, with a post exposure period of 2 days and during 20 days for rats, with a post exposure period of 5 days.
GLP compliance:
yes
Limit test:
no
Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
free access to food and water , temperature and humidity controlled quarters
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Pregnant female mice received 2.35 , 10.9, 50.6, 235 mg/kg bw /daydissolved in water from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receiving the highest dose.
Details on mating procedure:
one male was not permitted to impregnate more than one female: vaginal sperm plug: gestation day : 0
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
gd 6-gd 15
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
2.35 , 10.9, 50.6, 235 mg/kg bw /day
Basis:
nominal conc.
No. of animals per sex per dose:
20-24 pregnant females
Control animals:
yes, sham-exposed
Details on study design:
Pregnant female mice received 2.35 , 10.9, 50.6, 235 mg/kg bw /daydissolved in water from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receiving the highest dose.
Parental animals: Observations and examinations:
Maternal examinations
body weights on day 0, 6, 11, 15, 17 of gestation,
daily for appearancem behavior, , food consumption, , daily room temperature and humidity,
dams urogenital tract was examined after cesarian secrion
Postmortem examinations (parental animals):
Body weights were recorded during 17 days for mice, with a post exposure period of 2 days and during 20 days for rats,
with a post exposure period of 5 days.
No significant effects were observed on mice and rat’s survival and reproductive organs, or on offspring survival, weight, sex ratio and
congenital defects.
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
There were no treatment-related changes in precoital time, mating index, fertility index and pregnancy index.Results for F0- Precoital time, fertility and mating data: There were no statistically significant differences compared with the controls.- Gross findings: There were no chemical- related findings in all treatment groups.- Histopathological findings: There were no chemical- related findings in all treatment groups.
Dose descriptor:
NOAEL
Effect level:
235 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The NOEL values for parental/maternal and F1 offspring could be established as > 235 mg KCl/kg bw/day
Dose descriptor:
NOAEL
Effect level:
123 mg/kg bw/day
Based on:
test mat.
Remarks:
as potassium
Sex:
male/female
Basis for effect level:
other: The NOEL values for parental/maternal and F1 offspring could be established as > 235mg KCl/kg bw/day (corresponding to > 123 mg K+/kg bw/day)
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
No significant effects were observed on mice and rat’s survival and reproductive organs, or on offspring survival, weight, sex ratio and
congenital defects.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
235 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The NOEL values for parental/maternal and F1 offspring could be established as > 235mg KCl/kg bw/day
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
123 mg/kg bw/day
Based on:
test mat.
Remarks:
as potassium
Sex:
male/female
Basis for effect level:
other: The NOEL values for parental/maternal and F1 offspring could be established as > 235mg KCl/kg bw/day (corresponding to > 123 mg K+/kg bw/day)
Reproductive effects observed:
not specified
Conclusions:
Studies to the reproduction of Potassium oxide are not available. Based on the results of corresponding potassium salts like KCl , effects in non-irritating doses/concentrations to reproduction or development are not expected for Potassium oxide. The calculated NOAEL for the potassium ion is approx. 123 mg/kg bw.

Executive summary:

Studies to the reproduction of Potassium oxide are not available. Based on the results of corresponding potassium salts like KCl , effects in non-irritating doses/concentrations to reproduction or development are not expected for Potassium oxide. The calculated NOAEL for the potassium ion is approx. 123 mg/kg bw.

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
QSAR prediction: Accepted Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Qualifier:
according to
Guideline:
other: Estrogen Receptor Binding method
Principles of method if other than guideline:
This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.
GLP compliance:
no
Remarks:
not applicable. QSAR model
Limit test:
no
Species:
other: fish and mammals.
Strain:
other: QSAR model
Sex:
not specified
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Details on exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Parental animals: Observations and examinations:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
No binding to Estrogen Receptor Alpha (Log RBA <-3) for the Potassium oxide (CAS# 12136-45-7 )
Dose descriptor:
other: QSAR model
Effect level:
< -3 other: Log RBA
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
other: No binding to Estrogen Receptor Alpha (Log RBA <-3) for the Potassium oxide (CAS# 12136-45-7 )
Remarks on result:
other: Generation: QSAR model (migrated information)
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
No binding to Estrogen Receptor Alpha (Log RBA <-3) for the Potassium oxide (CAS# 12136-45-7 ) and therefore Potassium oxide does not cause reproductive toxicity.
Dose descriptor:
other: QSAR model
Generation:
F1
Effect level:
< -3 other: Log RBA
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
other: No binding to Estrogen Receptor Alpha (Log RBA <-3)
Remarks on result:
other: Generation: QSAR model
Reproductive effects observed:
not specified

No binding to Estrogen Receptor Alpha (Log RBA <-3) for the Potassium oxide (CAS# 12136-45-7 ) and therefore Potassium oxide does not cause reproductive toxicity.

Conclusions:
No binding to Estrogen Receptor Alpha (Log RBA <-3) for the Potassium oxide (CAS# 12136-45-7 )and therefore Potassium oxide does not cause reproductive toxicity.
Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels
Type of information:
other: Published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
A one generation study with female mice and rats exists for KCl. Doses of 2.35 – 235 mg/kg bw/day in mice and 3.1 – 310 mg/kg bw/day in rats were administered to groups of 21-24 animals by single daily oral intubation. Body weights were recorded during 17 days for mice, with a post exposure period of 2 days and during 20 days for rats, with a post exposure period of 5 days.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
free access to food and water , temperature and humidity controlled quarters
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Pregnant female rats received 3.1, 14.4, 66.8, 310.0 mg/kg bw /day from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receiving the highest dose. Sacrifice of all dams on day 20 of gestation.
Details on mating procedure:
one male was not permitted to impregnate more than one female: vaginal sperm plug: gestation day : 0
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
gd 6-gd 15
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
3.1, 14.4, 66.8, 310.0 mg/kg bw /day
Basis:
nominal conc.
No. of animals per sex per dose:
20-23 pregnant females
Control animals:
yes, sham-exposed
Details on study design:
Pregnant female rats received 3.1, 14.4, 66.8, 310.0 mg/kg bw /day from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receiving the highest dose. Sacrifice of all dams on day 20 of gestation.
Parental animals: Observations and examinations:
Maternal examinations
body weights on day 0, 6, 11, 15, 17 of gestation,
daily for appearancem behavior, , food consumption, , daily room temperature and humidity,
dams urogenital tract was examined after cesarian secrion
Postmortem examinations (parental animals):
Body weights were recorded during 17 days for mice, with a post exposure period of 2 days and during 20 days for rats,
with a post exposure period of 5 days.
No significant effects were observed on mice and rat’s survival and reproductive organs, or on offspring survival, weight, sex ratio and
congenital defects.
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
There were no treatment-related changes in precoital time, mating index, fertility index and pregnancy index.Results for F0- Precoital time, fertility and mating data: There were no statistically significant differences compared with the controls.- Gross findings: There were no chemical- related findings in all treatment groups.- Histopathological findings: There were no chemical- related findings in all treatment groups.
Dose descriptor:
NOAEL
Effect level:
310 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The NOEL values for parental/maternal and F1 offspring could be established as > 310 mg KCl/kg bw/day
Dose descriptor:
NOAEL
Effect level:
162 mg/kg bw/day
Based on:
test mat.
Remarks:
as potassium
Sex:
male/female
Basis for effect level:
other: The NOEL values for parental/maternal and F1 offspring could be established as > 310mg KCl/kg bw/day (corresponding to > 162 mg K+/kg bw/day)
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
No significant effects were observed on mice and rat’s survival and reproductive organs, or on offspring survival, weight, sex ratio and
congenital defects.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
310 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The NOEL values for parental/maternal and F1 offspring could be established as > 310mg KCl/kg bw/day
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
162 mg/kg bw/day
Based on:
test mat.
Remarks:
as potassium
Sex:
male/female
Basis for effect level:
other: The NOEL values for parental/maternal and F1 offspring could be established as > 310mg KCl/kg bw/day (corresponding to > 162 mg K+/kg bw/day)
Reproductive effects observed:
not specified
Conclusions:
Studies to the reproduction of Potassium oxide are not available. Based on the results of corresponding potassium salts like KCl , effects in non-irritating doses/concentrations to reproduction or development are not expected for Potassium oxide. The calculated NOAEL for the potassium ion is approx. 164 mg/kg bw.

Executive summary:

Studies to the reproduction of Potassium oxide are not available. Based on the results of corresponding potassium salts like KCl , effects in non-irritating doses/concentrations to reproduction or development are not expected for Potassium oxide. The calculated NOAEL for the potassium ion is approx. 164 mg/kg bw.

Endpoint:
two-generation reproductive toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
 
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
65.22 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Inhalation exposure:
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat
1500 mg/kg bw/day
÷1.15m3/kgbw
÷20m3/rat
NOAECrat 65.22 mg/m3
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
37.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Dermal exposure:
There are no dermal reproduction studies available.
For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
corrected dermal NOAEL= oral NOAEL
1500 mg/kg bw/day x 0.025 kg =
NOAELrat = 37.5 mg/kg bw/day

Additional information

Alternatively and more conveniently Potassium oxide is synthesized by heating potassium nitrate with metallic potassium:

2 KNO3 + 10 K → 6 K2O + N2

Therefore, the health effects ofpotassium nitrateneed to be considered in the assessment of Potassium oxide

 

Oral exposure

In reproductive toxicity study performed according to the reproduction/developmental toxicity screening test [OECD TG 422] under GLP.

No significant effects were observed on rat’s survival and reproductive organs, or on offspring survival, weight, sex ratio and congenital defects. There were no treatment-related deaths and no signs of overt clinical toxicity. There were no effects on body weight, food consumption, or food efficiency. Mating performance and fertility were unaffected by treatment. All animals mated within 4 days. There were no treatment-related effects on gestation length, gestation index, litter size, offspring survival indices, sex ration, offspring bodyweight, or macropathology for offspring.

NOAEL: 1,500 mg/kg/day (general toxicity)

              1,500 mg/kg/day (reproduction/developmental toxicity)

LOAEL: No adverse effects were seen on general toxicity endpoints. No adverse effects were seen on reproduction/developmental toxicity endpoints.

            

 NOAELrat  =1500 mg/kg bw/day

Dermal exposure:

There are no dermal reproduction studies available.

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

1500 mg/kg bw/dayx0.025 kg =                  

 NOAELrat  = 37.5mg/kg bw/day

Inhalation exposure:

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.

NOAEL rat             

 1500mg/kg bw/day

÷1.15m3/kgbw

÷20m3/rat

NOAECrat     65.22 mg/m3 

 


Short description of key information:
There are conclusive but not suffcient data for the classification of substance Potassium oxide/Dipotassium oxide with regard to reproduction.
Non-ER binder due to non-cyclic molecular structure. Dipotassium oxide have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Dipotassium oxide does not cause reproductive toxicity.
It is concluded that the substance Potassium oxide/Dipotassium oxide does not meet the criteria to be classified for human health hazards for Reproductive toxicity.

Justification for selection of Effect on fertility via inhalation route:
Inhalation exposure:
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat
1500 mg/kg bw/day
÷1.15m3/kgbw
÷20m3/rat
NOAECrat 65.22 mg/m3

Effects on developmental toxicity

Description of key information
There are conclusive but not suffcient data for the classification of substance  Potassium oxide/Dipotassium oxide  with regard to Developmental toxicity / teratogenicity 
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
other: Published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
Pregnant female rats received 3.1 , 14.4, 66.8, 310.0 mg/kg bw /day from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receiving the highest dose.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
free access to food and water , temperature and humidity controlled quarters
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Pregnant female mice received 2.35 , 10.9, 50.6, 235 mg/kg bw /daydissolved in water from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receiving the highest dose.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
one male was not permitted to impregnate more than one female: vaginal sperm plug: gestation day : 0
Duration of treatment / exposure:
gd 6-gd 15
Frequency of treatment:
daily
Duration of test:
until gd 20
No. of animals per sex per dose:
20-23 pregnant females
Control animals:
yes, sham-exposed
Details on study design:
Pregnant female rats received 3.1, 14.4, 66.8, 310.0 mg/kg bw /day from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receiving the highest dose. Sacrifice of all dams on day 20 of gestation.
Maternal examinations:
body weights on day 0, 6, 11, 15, 17 of gestation,
daily for appearancem behavior, , food consumption, , daily room temperature and humidity,
dams urogenital tract was examined after cesarian secrion
Ovaries and uterine content:
sex, number of corpora lutea, implantation sites , resorptions sites, live and dead fetuses
Fetal examinations:
live and dead fetuses, body weight of live pups, gross examination for the presence of external abnormalities: one third underwent visceral examinations and two third skeletal examination
Statistics:
no data
Indices:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
The administration of up to 310 mg/kg bw of KCl to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal survival
Dose descriptor:
NOAEL
Effect level:
ca. 310 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
ca. 310 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The administration of up to 310 mg/kg bw of KCl to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal of fetal survival. The number of abnormalities seen in either soft or skelital tissues of the test groups did not differ from the numger occurring sponateously in the sham treated controls
Dose descriptor:
NOAEL
Effect level:
310 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The administration of 3.1 up to 310.0 mg/kg bw of KCl to pregnant Wistar rats for 10 consecutive days(gd 6 -gd15, sacrifice on gd20) had no clearly discernible effect on nidation or on maternal of fetal survival. The number of abnormalities seen in either soft or skelital tissues of the test groups did not differ from the numger occurring sponateously in the sham-treated controls .
Executive summary:

The administration of 3.1 up to 310.0 mg/kg bw of KCl to pregnant Wistar rats for 10 consecutive days(gd 6 -gd15, sacrifice on gd20) had no clearly discernible effect on nidation or on maternal of fetal survival. The number of abnormalities seen in either soft or skelital tissues of the test groups did not differ from the numger occurring sponateously in the sham-treated controls .

Endpoint:
developmental toxicity
Type of information:
other: Published data
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
Principles of method if other than guideline:
Pregnant female mice received 2.35 , 10.9, 50.6, 235 mg/kg bw /day from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receivint the highest dose.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
free access to food and water , temperature and humidity controlled quarters
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Pregnant female mice received 2.35 , 10.9, 50.6, 235 mg/kg bw /daydissolved in water from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receivint the highest dose.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
one male was not permitted to impregnate nore than one female: vaginal sperm plug: gestation day : 0
Duration of treatment / exposure:
gd 6-gd 15
Frequency of treatment:
daily
Duration of test:
until gd 17
No. of animals per sex per dose:
20-24 pregnant females
Control animals:
yes, sham-exposed
Details on study design:
Pregnant female mice received 2.35 , 10.9, 50.6, 235 mg/kg bw /day from gd 6 to gd 15 by gavage. the controls were sham treated with the vehicle at a level equivalent to the group receivint the highest dose.
Maternal examinations:
body weights on day 0, 6, 11, 15, 17 of gestation,
daily for appearancem behavior, , food consumption, , daily room temperature and humidity,
dams urogenital tract was examined after cesarian secrion
Ovaries and uterine content:
sex, number of corpora lutea, implantation sites , resorptions sites, live and dead fetuses
Fetal examinations:
live and dead fetuses, body weight of live pups, gross examination for the presence of external abnormalities: one third underwent visceral examinations and two third skeletal examination
Statistics:
no data
Indices:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
The administration of up to 235 mg/kg bw of KCl to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal survival
Dose descriptor:
NOAEL
Effect level:
ca. 235 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
ca. 235 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The administration of up to 235 mg/kg bw of KCl to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal of fetal survival. The number of abnormalities seen in either soft or skelital tissues of the test groups did not differ from the numger occurring sponateously in the sham treated controls
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The administration of 2.35 up to 235 mg/kg bw of KCl to pregnant CD-1 mice for 10 consecutive days(gd 6 -gd15, sacrifice gd17) had no clearly discernible effect on nidation or on maternal of fetal survival. The number of abnormalities seen in either soft or skelital tissues of the test groups did not differ from the number occurring sponateously in the sham-treated controls .
Executive summary:

The administration of 2.35 up to 235 mg/kg bw of KCl to pregnant CD-1 mice for 10 consecutive days(gd 6 -gd15, sacrifice gd17) had no clearly discernible effect on nidation or on maternal of fetal survival. The number of abnormalities seen in either soft or skelital tissues of the test groups did not differ from the number occurring sponateously in the sham-treated controls .

Endpoint:
developmental toxicity
Type of information:
other: Published data
Adequacy of study:
key study
Study period:
January 7, 2002 – October 14, 2002 (In-life study dates Jan 8, 2002 – Feb 23, 2002)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
According to OECD 422 and GLP procedures. Alternatively and more conveniently Potassium oxide is synthesized by heating potassium nitrate with metallic potassium: 2 KNO3 + 10 K → 6 K2O + N2 Therefore, the health effects of potassium nitrate need to be considered in the assessment of Potassium oxide
Qualifier:
according to
Guideline:
other: OECD 422
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC
- Age at study initiation: males were 64 days of age on day of arrival; females were 61 days of age on day of arrival
- Weight at study initiation: 225 – 325 grams for male rats; 161 – 219 for female rats
- Fasting period before study:
- Housing: Animals were individually housed except for during the cohabitation and lactation period in wire mesh suspended stainless steel cages which conformed with GLP requirements, During cohabitation each pair of rats were housed in the male rat’s cage. Beginning no later than Day 20 of gestation, female rats were individually housed in polyethylene shoebox cages containing nesting material with wire mesh lids. Each dam and litter was housed in a common nesting box during the lactation/postnatal period.
- Diet (e.g. ad libitum): Purina Certified Rodent Diet #5002; as libitum
- Water (e.g. ad libitum): automatic dispenser; ad libitum and when females and litters were housed in shoebox cages via water bottle; ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 – 22 C
- Humidity (%): 43 – 66 %
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hrs
Route of administration:
oral: gavage
Details on exposure:
Dose Calculations: Individual doses were calculated based on the most recent weekly body weights and were adjusted each week to maintain the targeted dose level for all rats in the General Toxicity groups (i.e.., mg/kg/day). For female rats in the reproduction groups, individual oses were calculated based on the most recent body weights and were adjusted to maintain the targeted dose level (i.e., mg/kg/day). All doses were administered by volume of 10 ml/kg after correcting for concentration of the text mixture. Control animals received the vehicle only at the same volume as the test groups.
Dose preparations: The test substance (011101-3D) was ground in a Krups coffe mill (model 203) prior to use and again receipt of additional test substance (010122-1D). A quantity sufficient to cover the grinding blade was added to the coffee mill and ground to a fine powder. Appropiate amounts of ground test material were accurately weighed into a 100 ml volumetric flask and diluted to volume with distilled water for each of the low, mid and high concentrations. Given that there was visual evidence (i.e. settling of test substance to bottom of cup) of a small amount of precipitate, the dosing mixtures were constantly stirred on a magnetic stir plate while being sampled to dose the test animals during the study.
Dose frequency: Each animal was dosed by oral intubation using a stainless steel balltipped gavage needle attached to an appropriate syringe. Dose administration was daily (7 days/week) for all adult animals as follows:
Male rats:
- Reproduction/General Toxicity Groups: During two-week premating and two-week mating periods for at least 28 days of exposure.

Female rats:
-Reproduction Groups: During two-week premating, two-week mating, gestational and lactational periods.
-General Toxicity GFroups: For at least 28 days of exposure

- Rate of preparation of diet (frequency): Not applicable, route of administration of test substance is via gavage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance was assumed to be homogenous and stable at the time drawn by syringe to dose the test animals. Analysis of dosing mixtures, therefore, were limited to concentration verification of representative preparations intended for the control, low, intermediate and high dose levels in the study. Representative dosing mixtures of each concentration during the study were provided to the analytical department at three time points during the study (prior to animal exposure, near the middle (Test days 24 and 28) and near the end of the study (Test day 45). Vehicle control samples were inadvertently not submitted for analysis. Each dose preparation was evaluated by flame atomic absorption spectroscopy for total potassium (SOAC Official Method 975.03)(1988). A reference standard of potassium (999 ug/ml) , supplied by EM Science, was used for calibration.
Details on mating procedure:
no data
Duration of treatment / exposure:
Animals on the study were divided between two subgroups (toxicity and reproductive subgroups). The exposure period for males and females in the toxicity subgroup was 28 days. The exposure period for reproductive subgroup males was at most 28 days. The exposure period for reproductive subgroup females was at most 53 days (14 days pre-mating, 14 days mating, and gestational and lactational periods up to lactation day 4).
Frequency of treatment:
daily
Duration of test:
tox group: 28 days
repro group: 53 days
No. of animals per sex per dose:
5 males/group
10 females/group
Control animals:
yes, concurrent vehicle
Details on study design:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for viability and cage-side observations were performed daily during acclimation, premating and mating, gestation, and lactation periods, except when scheduled detailed observations were conducted. All observations were recorded.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Observations were performed and recorded at least once during the acclimation period for all male and female rats. Observations were performed and recorded approximately once per week during the premating and mating periods for females of the reproduction groups during the gestational days (GD7, GD14 and GD20) and lactational (LD4 only) periods. Female rats were evaluated for adverse clinical signs during parturition. Maternal behavior was checked on LD0 and LD4 and recorded. The date and clock time of all observations and/or mortality checks was recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded at least twice during the acclimation period (including the day after receipt) before pairing and mating. All male rats were weighed weekly during the premating and mating periods and at the time of sacrifice. Mated females were weighted on GD0, 7, 14 and 20, and on the day of delivery (LD0) and LD4 (prior to terminal sacrifice). Females showing no evidence of mating were assigned a GD0 after cessation of cohabitation and body weights were measured accordingly. Females in the General Toxicity Groups were weighed weekly and at the time of sacrifice. Body weight gains were calculated for males and females during each appropriate interval.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Although not a feeding study, food consumption was determined weekly during the premating period (no mating period) for all males and females. Individual food consumption was measured and recorded weekly thereafter for the females in the general toxicity groups and during the gestational period for the females in the reproductive groups. Food consumption was also recorded on LD0 and LD4. The data were then used to calculate food efficiency for the associated intervals.

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: Data from food consumption were used to determine food efficiency for associated intervals.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: See detailed clinical observations
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 28 of treatment
- Anaesthetic used for blood collection: Yes. (Isoflourane anesthesia ) collected via orbital sinus bleeding.
- Animals fasted: Yes, 18 hours prior to blood collection
- How many animals: 5 males and 5 females/dose level
- Parameters examined: hematocrit, hemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, prothrombin time and activated partial thromboplastin time.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on Day 28 of treatment
- Animals fasted: Yes. 18 hours prior to blood collection
- How many animals: 5 males and 5 females/dose level
- Parameters examined: calcium, phosphorus, chloride, sodium, potassium, fasting glucose, serum alanine aminotransferase (SGPT), serum aspartate aminotransferase (SGOT), gamma glutamyl transpeptidase, urea nitrogen, albumin, blood creatinine, total bilirubin, total serum protein, globulin, total cholesterol, alkaline phosphatase and magnesium measurements.

URINALYSIS: Yes / No / No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters examined:

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during the final days of treatment
- Dose groups that were examined: Five male and five females/dose group (including controls).
- Battery of functions tested: sensory activity / grip strength / motor activity: excitability, autonomic function, gait and sensorimotor coordination (open field and manipulative evaluations), reactivity and sensitivity (elicited behavior) and other abnormal clinical signs including but not limited to convulsions, tremors, unusual or bizarre behavior, emaciation, dehydration, and general appearance. The rats were observed in random without the observer aware of the dose group.

Motor activity was also evaluated. Each animal was evaluated for a single one-hour phase, with photobeam counts accumulated over six, 10-minute intervals. Total movements (consisting of fine and active movements) was considered an appropriate measure for the assessment of potential behavior effects in this screening level study.)
Maternal examinations:
Necropsy: Gross necropsy of all males and females included an initial examination of
external surfaces and orifices, as well as the cranial, thoracic and abdominal cavities and
their contents. Rats were examined for gross lesions. Gross lesions were retained in
neutral buffered. 10% formalin (NBF).
• Reproductive Groups: Special attention was paid to the organs of the
reproductive system. For male rats, the testes and epididymides. seminal vesicles
with coagulating gland and prostate were retained. The testes and epididymides
were weighed. The testes were fixed in Bouin's solution for 4-12 hours
(depending on size) before being retained in 70% alcohol For females, special
care was taken to examine the uterus for the presence of conceptuses .. For each
female, the ovaries were weighed; the ovaries, uterus and accompanying
structures, and a mammary gland were retained in NBF. Subsequently, the fixed
uteruses from all adult female rats (including those that did not deliver litters and
those that delivered pups) were stained with potassium ferricyanide to confirm
pregnancy status and to determine post-implantation toss.

Rats were evaluated for gross lesions. Pregnancy status and uterine contents of
female rats were recorded.. Aborted fetuses and/or delivered pups were
examined to the extent possible. Organs and tissues were excised, weighed,
preserved and/or stained and implantation sites counted as described for 1hose
animals sacrificed by design.

• General Toxicology Groups: At scheduled sacrifice, all survivors were
euthanized by exsanguination from the abdominal aorta under isoflourane
anesthesia. All animals were subjected to a full necropsy that included
examination of the external surface of the body, all orifices and the thoracic.
abdominal and cranial cavities and their contents. The liver, kidneys, adrenals,
brain, heart, thymus, spleen. ovaries, testes and epididymides (of all animals
sacrificed by design) were weighed wet as soon as possible after dissection to
avoid drying. The following organs and tissues from all animals were preserved
in NBF for possible future histopathological examination: all gross lesions,
lungs, brain~ including sections of the medulla/pons. cerebellar cortex and
cerebral cortex, spinal cord (3 levels: cervical, mid-thoracic, and lumbar), eyes,
pituitary. thyroid/parathyroid, thymus, trachea, heart. sternum with bone marrow,
salivary glands, liver, spleen, kidneys, adrenals, pancreas, ovaries, testes, uterus
(with attached urinary bladder, cervix and vagina), accessory sex organs
(epididymides, prostate, and seminal vesicles). female mammary gland., skin.
aorta. esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum,
representative lymph node, and peripheral nerve (sciatic).

HISTOPATHOLOGY: Yes
Organs: Histopathologic examination was performed on the preserved organs and tissues of the Reproductive and General Toxicity Group animals from the control (Groups I and II) and high dose (Groups VII and VIII). In addition, gross lesions of potential toxicological significance noted in any test groups were also examined. Microscopic findings were graded.
Statistics:
Mean and standard deviations were calculated for all quantitative data. Except for clinical pathology data were the contract laboratory, Huntingdon Life Sciences, elected to use statistics to aid in the data interpretation; no further statistical treatment of the study was conducted due to small group sizes.
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
>= 1 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Remarks on result:
other: Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified

NOAEL:

1,500 mg/kg/day (general toxicity)

1,500 mg/kg/day (reproduction/developmental toxicity)

LOAEL:

No adverse effects were seen on general toxicity endpoints.

No adverse effects were seen on reproduction/developmental toxicity endpoints

Toxicity subgroup: There were no treatment-related deaths and no signs of overt clinical toxicity. There were no effects on body weight, food consumption, or food efficiency. Functional observational battery (FOB) and motor activity tests identified no treatment-related changes in behavior, function, or motor activity. A slight increase in blood urea nitrogen was observed in male and female rats at 1,500 mg/kg/day and in female rats at 750 mg/kg/day. Although outside the range of the historical control, the absence of other indicators of renal dysfunction (e.g., creatinine) discounted the clinical significance of this endpoint. Minimal changes in electrolyte levels in male rats (e.g., 10% decrease in potassium, 4% decrease in calcium, and 22% increase in phosphorus) and female rats (3% decrease in chloride, 4% decrease in magnesium) were observed at 1,500 mg/kg/day. These changes were within the range of historical control and were not considered to be of biological significance. No treatment-related histopathological changes were reported.

Reproductive subgroup: There were no treatment-related deaths and no signs of overt clinical toxicity. There were no effects on body weight, food consumption, or food efficiency. Mating performance and fertility were unaffected by treatment. All animals mated within 4 days. There were no treatment-related effects on gestation length, gestation index, litter size, offspring survival indices, sex ration, offspring bodyweight, or macropathology for offspring.

WATER CONSUMPTION AND COMPOUND INTAKE

There were no effects of test-substance treatment on food consumption in males.

There were no effects of food consumption on females during pre-mating; during

Weeks 3, 4, and 5 for females in the General Toxicity Group; or during gestation and

lactation. Food consumption was not measured during the mating period. Food

efficiency was also unaffected by treatment.

ORGAN WEIGHTS:

Mean organ weights and organ-to-body weight ratios for both the Reproduction and

General Toxicity test groups, in general, were considered comparable to their

respective control groups. Any slight increases or decreases from the control were

incidental, not dose-related and judged not to be of toxicological importance.

GROSS PATHOLOGY:

There were a number of gross observations correlated to microscopic findings. The

dilatation of the uterus (horns) observed in several female rats from the General

Toxicology Group (Group II", Animal #8133 and 8134, Group VIII - Animal #8205,

8206, 8207 and 8208) was considered to be a function of the· estrus stage (generally

proestrus, but sometimes early estrus). These gross observations and others, along

with their microscopic correlates, were all considered incidental background findings

not attributable to administration of the test substance.

Conclusions:
NOAEL:
1,500 mg/kg/day (general toxicity)
1,500 mg/kg/day (reproduction/developmental toxicity)
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
310 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
13.48 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Inhalation exposure:
There are no Inhalation Developmental studies available.
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat
310 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 13.48 mg/m3
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
7.75 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Dermal exposure:
There are no dermal Developmental studies available.
For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
corrected dermal NOAEL= oral NOAEL
310 mg/kg bw/day x 0.025 kg =
NOAELrat = 7.75 mg/kg bw/day
Additional information

Oral exposure

Potassium chloride (KCl) is the most common source of Potassium oxide (K2O).

Therefore, the health effects ofpotassiumchlorideneed to be considered in the assessment of Potassium oxide

The administration of 3.1 up to 310.0 mg/kg bw of KCl to pregnant Wistar rats for 10 consecutive days (gd 6 -gd15, sacrifice on gd20) had no clearly discernible effect on nidation or on maternal of fetal survival. The number of abnormalities seen in either soft or skelital tissues of the test groups did not differ from the numger occurring sponateously in the sham-treated controls .

NOAELrat  = 310 mg/kg bw/day

Inhalation exposure:

There are no Inhalation Developmental studies available.

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.

NOAEL rat             

 310 mg/kg bw/day

÷1.15 m3/kgbw

÷20m3/rat

NOAECrat    13.48 mg/m3

Dermal exposure:

There are no dermal Developmental studies available.

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

310 mg/kg bw/dayx0.025 kg =                  

 NOAELrat  = 7.75 mg/kg bw/day

Toxicity to reproduction: other studies

Link to relevant study records

Referenceopen allclose all

Endpoint:
toxicity to reproduction: other studies
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint:
toxicity to reproduction: other studies
Type of information:
other: Published data
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:
other: OECD TG 453
Deviations:
yes
Remarks:
prolongation of treatment time up to 30 months and only one dose used
GLP compliance:
not specified
Type of method:
in vivo
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5 weeks
- Housing: groups of 5 of same sex and same treatment group
- Diet ad libitum
- Water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 35-70
- Air changes (per hr):10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
male and female rats were fed diets containing 0 or 3 % KCL over a total period of 30 months
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
no details given

Duration of treatment / exposure:
10 rats/sex/group: 13 weeks
15 rats/sex/group; 18 months
50 rats/sex/group: 30 months
Frequency of treatment:
coninuously in diet
Duration of test:
30 months
Remarks:
Doses / Concentrations:
3 % in diet
Basis:
nominal in diet
No. of animals per sex per dose:
10 rats/sex/group: 13 weeks
15 rats/sex/group; 18 months
50 rats/sex/group: 30 months
Control animals:
yes, concurrent no treatment
Details on study design:
male and female rats were fed diets containing 0 or 3 % KCL over a total period of 30 months: after 13 weeks 10 rats/sex/group were examined , after 18 months 15 rats/sex/group were examined and after 30 months 50 rats/sex / group were examined
Statistics:
ANOVA /LSD test, Mann-Whitney U-test. two-sided Fisher exactprobability test
Dose descriptor:
conc. level:
Effect level:
ca. 3 other: % in diet
Based on:
other: nominal
Sex:
male/female
Basis for effect level:
other: no effects on reproductive organs were reported
for general toxicity see section Repeated dose toxicity
No effects on reproductive organs were reported

BODY WEIGHT AND WEIGHT GAIN (graphic only)

30 months: mean body weights were decreased in males and females compared to controls

18 months: mean body weights in males were decreased when compared to controls

13 weeks no growth depression was observed

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)

due to the reduction of feed intake the mean test substance intake decreased in time:

--13 w treatment males 29.9 mmol/kg bw , females: 35.2 mmol/kg bw

--18 month treatment, males: 20.8 mmol/kg bw , females 24.7 mmol/kg bw

--30 months treatment, males:19.5 mmol/kg bw , females:.22,6 mmol/kg bw

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)

water intake was increased throughout the studies by ca 25 % in males and females

HAEMATOLOGY

blood gas analysis: base exess was not affected by feeding KCl

there were no consistent or treatment related effects on red blood cell variables , clotting potential or total and differential blood cell count

CLINICAL CHEMISTRY

Potassium levels in plasma were generally increased although the difference to the concurrent control was not significant (data not shown)

URINALYSIS

Urinary pH was not influenced by the feeding of KCl

the volume of the urine collected during 24 hours was generally increased in rats fed KCL

urinary potassium excretion was significantly increased in all groups that were fed KCl

GROSS PATHOLOGY/ ORGAN WEIGHTS

-With KCl the relative kidney weights tended to be increased but were not consistent

-there was no consistent or treatment related changes in the weights of the liver, spleen, ovaries , pituitary, thyroid, thymus or heart

-The analysis of femur ath the end of the studies did not reveal any effects of femur weight, calcium content or on total bone substance

-macroscopic examinations at necropsy did not reveal significant differences among the treatment group and the control group,

HISTOPATHOLOGY: NON-NEOPLASTIC

30 month-treatment:

in the adrenals, zona glomerulosa: hypertrophy in 24/50 treated rats versus 4/50 in controls,

in the urinary bladder: cystitis (males: 3/59; females 3/50) and single epithelial hyperplasia (males 3/50; females 2/50)

Conclusions:
Male and female Wistar rats were fed diets containing 0 or 3 % KCL over a total period of 30 months: Examination after 13 weeks (10 rats/sex/group), after 18 months (15 rats/sex/group) and after 30 months (50 rats/sex /group). Due to the reduction of feed intake the mean test substance intake and mean body weight decreased in time. After 30 months treatment, reproductive organs on males and females were not affected by treatment.
Executive summary:

Male and female Wistar rats were fed diets containing 0 or 3 % KCL over a total period of 30 months: Examination after 13 weeks (10 rats/sex/group), after 18 months (15 rats/sex/group) and after 30 months (50 rats/sex /group). Due to the reduction of feed intake the mean test substance intake and mean body weight decreased in time. After 30 months treatment, reproductive organs on males and females were not affected by treatment.

Endpoint:
toxicity to reproduction: other studies
Type of information:
other: Published data
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
Principles of method if other than guideline:
Groups of male F344/Slc rats received different doses of KCl in feed over a period of 2 years and were observed for clinical signs and mortality and were examined for gross and histopathological changes at the end of the treatment period
GLP compliance:
not specified
Type of method:
in vivo
Species:
rat
Strain:
other: F344/Slc
Sex:
male
Details on test animals and environmental conditions:
no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
male and female rats were fed diets containing 0 or 3 % KCL over a total period of 30 months
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no details given

Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Duration of test:
2 years
Remarks:
Doses / Concentrations:
0, 0.25, 1, 5 % in diet (corresponding to 0, 110, 450, 1820 mg/kg bw/day
Basis:
nominal in diet
No. of animals per sex per dose:
50
Control animals:
yes, concurrent no treatment
Statistics:
no data
Dose descriptor:
other: no effects on reproductive organs
Effect level:
>= 110 - <= 1 820 mg/kg bw/day (nominal)
Based on:
other: nominal
Sex:
male
Basis for effect level:
other: No changes were reported in the absolute and relative organ weights of the testesm seminal vesicle and prostate
Conclusions:
Groups of male F344/Slc rats received 0, 0.25, 1, 5 % KCl in diet (corresponding to 0, 110, 450, 1820 mg/kg bw/day) over a period of 2 years and were observed for clinical signs and mortality and were examined for gross and histopathological changes at the end of the treatment period. No changes were reported in the absolute and relative organ weights of the testes, seminal vesicle and prostate or of histopathological changes of these organs .
Executive summary:

Groups of male F344/Slc rats received 0, 0.25, 1, 5 % KCl in diet (corresponding to 0, 110, 450, 1820 mg/kg bw/day) over a period of 2 years and were observed for clinical signs and mortality and were examined for gross and histopathological changes at the end of the treatment period. No changes were reported in the absolute and relative organ weights of the testes, seminal vesicle and prostate or of histopathological changes of these organs .

Additional information

Based upon the toxicological data available, including the reproduction toxicity study available, and taking account of animal welfare consideration, there is no evidence that the substance is likely to have any reproduction toxicity effect. It is therefore considered not scientifically justified to undertake any further reproductive toxicity study in animals.

Justification for classification or non-classification

Based on the hazard assessment of Potassium oxide/Dipotassium oxide in section 2.1 and 2.2. in IUCLID 5.4., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health” and according to the criteria described in Directive 67/548 and in the CLP Regulation:

Directive 67/548

Toxicity to reproduction/development

Repr. Cat. 1; R61 May cause harm to the unborn child.

Repr. Cat. 2; R61 May cause harm to the unborn child.

Repr. Cat. 3; R63 Possible risk of harm to the unborn child.

Toxicity to reproduction/fertility

 Repr. Cat. 1; R60 May impair fertility.

Repr. Cat. 2; R60 May impair fertility.

Repr. Cat. 3; R62 Possible risk of impaired fertility

 

CLP

Reproductive toxicity

Repr. 1A

Repr. 1B

Repr. 2

H360: May damage fertility or the unborn child <state specific effect if known > <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

H361: Suspected of damaging fertility or the unborn child <state specific effect if known> <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

 

 

 

It is concluded that the substance Potassium oxide/Dipotassium oxide does not meet the criteria to be classified for human health hazards for Reproductive toxicity