Dipotassium oxide

Endpoint summary

Description of key information

Oral repeated dose toxicity 
Potassium chloride (KCl) is the most common source of Potassium oxide (K2O). Therefore, the health effects of potassium chloride need to be considered in the assessment of Potassium oxide
Groups of male F344/Slc rats received 110, 450, 1820 mg/kg bw/day 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 (Imai 1961) The NOAEL was set 1820 mg/kg bw/day since nephritis was reported in all treatment groups as well as in the control group. With respect to the observed gastritis which is regarded to be a local effect a LOAEL(local) of 110 mg/kg bw/d was determined (Imai 1961, UNEP 2003). 
NOAEL -1820 mg/kg bw/day
  
Dermal repeated dose toxicity 
There are no dermal repeated 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 
1820 mg/kg bw/day x 0.025 kg =                   
 NOAELrat  = 45.5 mg/kg bw/day 
  
Inhalation repeated dose toxicity 
There are no Inhalation Repeated 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 
1820 mg/kg bw/day 
÷1.15 m3/kgbw 
÷20m3/rat 
NOAECrat     79.13 mg/m3

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

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:

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

Limit test:

no

Species:

rat

Strain:

other: F344/Slc

Sex:

male

Details on test animals or test system and environmental conditions:

no data to be identified because only abstract available

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Groups of male F344/Slc rats received different doses of KCl in feed over a period of 2 years

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 years

Frequency of treatment:

daily

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

Details on study design:

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

Positive control:

no

Observations and examinations performed and frequency:

survival, food consumption, blood pressure, body weight development
urinalysis: protein, glucose, keton, bilirubin, urobilinogen, pH
hematology: RBC, HB, Ht, MCV, HCH, MCHC, Pt, WBC
biochemical analysis: GOT, GPT, ALP, LDH, Ch-E, Na, K, Cl, Nu, Clu, Tp, Glu

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
absolue and relative organ weight: brain, pituitary, thymus, heart, right and leftlungs, linver, spleen, pancreas, right and left kidneys, right and leftadernals. right and left testes, seminal vesicles, prostrate
HISTOPATHOLOGY: Yes
heart, lung, liver, kidney, stomach, aorta
(grading of nephrosis +, ++, +++)

Other examinations:

no data

Statistics:

no data

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

MORTALITY:
after termination of the 2 year treatment period_
110, 450, 1820 mg/kg bw/day versus control:
18/50, 21/50, 8/50 versus 26/50
survival rate:
32/50, 29/50, 42/50 versus 24/50

HISTOPATHOLOGY: NON-NEOPLASTIC
KIDNEYS. nephritis
110, 450, 1820 mg/kg bw/day versus control:
32/32, 29/29, 42/42 versus 24/24
grading:
110 mg/kg: 23/32: +; 6/32: ++; 3/32: +++
450 mg/kg: 11/29:+; 6/29: ++; 12/29: +++;
1820 mg/kg: 28/42: +; 13/42: ++; 1/42: +++
control: 14/24: +; 6/24: ++; 4/24: +++

STOMACH.:
110, 450, 1820 mg/kg bw/day versus control:
gastritis
18/32, 18/29; 30/42 versus 6/24
ulcer
0/32, 2/29 , 2/42 versus 0/24

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
HISTORICAL CONTROL DATA (if applicable)
In tumerous lesions, testicular tumor developed with a high incidence in all groups and the incidence of pheochromocytoma in the adrenals was moderately high in all groups.
However the incidence and type of tumour in experimental and control group were comparable to those of spontaneous tumours in F344/Slc rats (data not shown). Therefore the tumours observed in this study were thought to be spontaneous in origin
OTHER FINDINGS

Dose descriptor:

NOAEL

Effect level:

ca. 1 820 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: The high mortality in all groups including controls (>50%) . nephritits was reported in all treatment groups as well as in the control group (UNEP 2003)

Dose descriptor:

LOAEL

Remarks:

local

Effect level:

ca. 110 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: With respect to gastritis which is regarded to be a local effect; UNEP 2003

Critical effects observed:

not specified

Conclusions:

Groups of male F344/Slc rats received 110, 450, 1820 mg/kg bw/day 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 (Imai 1961) The NOAEL was set 1820 mg/kg bw/day since nephritis was reported in all treatment groups as well as in the control group. With respect to the observed gastritis which is regarded to be a local effect a LOAEL(local) of 110 mg/kg bw/d was determined (Imai 1961, UNEP 2003).

Executive summary:

Groups of male F344/Slc rats received 110, 450, 1820 mg/kg bw/day 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 (Imai 1961) The NOAEL was set 1820 mg/kg bw/day since nephritis was reported in all treatment groups as well as in the control group. With respect to the observed gastritis which is regarded to be a local effect a LOAEL(local) of 110 mg/kg bw/d was determined (Imai 1961, UNEP 2003).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 820 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

79.13 mg/m³

Study duration:

chronic

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
1820 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 79.13 mg/m3

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

79.13 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Inhalation exposure:
There are no Inhalation Repeated 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
1820 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 79.13 mg/m3

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

45.5 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Dermal repeated dose toxicity
There are no dermal repeated 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
1820 mg/kg bw/day x 0.025 kg =
NOAELrat = 45.5 mg/kg bw/day

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

5.62 mg/cm²

Study duration:

subacute

Species:

rat

Additional information

Oral repeated dose toxicity

Potassium chloride (KCl)is the most common sourceofPotassium oxide(K2O).Therefore, the health effects of potassium chloride need to be considered in the assessment of Potassium oxide

Groups of male F344/Slc rats received 110, 450, 1820 mg/kg bw/day 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 (Imai 1961) The NOAEL was set 1820 mg/kg bw/day since nephritis was reported in all treatment groups as well as in the control group. With respect to the observed gastritis which is regarded to be a local effect a LOAEL(local) of 110 mg/kg bw/d was determined (Imai 1961, UNEP 2003).

NOAEL -1820 mg/kg bw/day

 

 

Dermal repeated dose toxicity

 

There are no dermal repeated 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

1820 mg/kg bw/dayx0.025 kg =                  

 NOAELrat  = 45.5 mg/kg bw/day

 

Inhalation repeated dose toxicity

 

There are no Inhalation Repeated 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

1820 mg/kg bw/day

÷1.15 m3/kgbw

÷20m3/rat

NOAECrat    79.13 mg/m3

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
The generic modification from the NOAELtest (in mg/kg of body weight) to NOAELmodified (in mg/cm2/day) will be
NOAELin mg/cm2 = ((dose in mg/kg bw)x (average animal weight in kg)) / Treated surface in cm2)
NOAELtest* 0.25/44.5= NOAELmodified

The highest dose not causing irritation/corrosion was 1000 mg/kg bw in dermal toxicity study in rats of Merkel, D.J., N. 2000.
the modified dose descriptor would be
NOAELmodified =1000 mg/kg*0.25 kg/44.5cm2=5.62 mg/cm2

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys; other: all gross lesions and masses

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: kidneys; other: all gross lesions and masses

Repeated dose toxicity: dermal - systemic effects (target organ) other: all gross lesions and masses

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 onInformation Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health”, according to the EU’s list of dangerous substances (OJEC No L200/130.7.99) and according to the criteria described in Directive 67/548 and in the CLP Regulation:

 

Directive 67/548

Repeated dose toxicity R33 Danger of cumulative effects. T; R48/23 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation. T; R48/23/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin. T; R48/23/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. T; R48/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin. T; R48/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed. T; R48/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure if swallowed. Xn; R48/20 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation. Xn; R48/20/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin. Xn; R48/20/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed. Xn; R48/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin. Xn; R48/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed. Xn; R48/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure if swallowed.

CLP

Repeated dose toxicity STOT Rep. Exp. 1 STOT Rep. Exp. 2 H372: Causes damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>. H373: May cause damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <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 Repeated dose toxicity