Cesium potassium fluoroaluminate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25.3 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

7.5

Dose descriptor starting point:

NOAEC

Value:

283 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

189.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m³/10 m³).

AF for dose response relationship:

1

Justification:

Not required, starting point is NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not necessary for the inhalation route

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

3

Justification:

Using a reduced factor of 3 (instead of 5) is justified because the critical effect is a local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution, metabolism and elimination play no/a minor role.

AF for the quality of the whole database:

1

Justification:

Database of good quality

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.14 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

6

Dose descriptor:

NOAEC

Value:

1.21 mg/m³

AF for dose response relationship:

1

Justification:

Not required, starting point is NOAEC

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not necessary for the inhalation route

AF for other interspecies differences:

1

Justification:

Humans are not considered more sensitive compared to rats and mice and an assessment factor of 1 is considered appropriate. Further explanations are given below in Additional information - Workers.

AF for intraspecies differences:

3

Justification:

Using a reduced factor of 3 (instead of 5) is justified because the critical effect is a local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution, metabolism and elimination play no/a minor role.

AF for the quality of the whole database:

1

Justification:

Database of good quality

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25.3 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

7.5

Dose descriptor starting point:

NOAEC

Value:

283 mg/m³

AF for dose response relationship:

1

Justification:

Not required, starting point is NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not necessary for the inhalation route

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

3

Justification:

Using a reduced factor of 3 (instead of 5) is justified because the critical effect is a local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution, metabolism and elimination play no/a minor role.

AF for the quality of the whole database:

1

Justification:

Database of good quality

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13.9 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

4 166.7 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Conversion into dermal NOAEL assuming 100% oral absorption and 0.72% dermal absorption for cesium potassium fluoroaluminate

AF for dose response relationship:

1

Justification:

Not required, starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from sub-acute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Default assessment factor for allometric scaling (rat to human)

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining differences

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

Database of good quality

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. The substance is classified for acute inhalation toxicity. For short term exposure to cesium potassium fluoroaluminate, a DNEL has been derived based on the results of a sensory irritation study with multiconstituent aluminium potassium fluoride according to the REACH guidance.

No data are available concerning local effects after repeated dermal contact with cesium potassium fluoroaluminate. Based on the read-across from multiconstituent aluminium potassium fluoride and cesium aluminium fluoride - complex, the substance is not considered to be irritating or sensitizing to the skin, while it is considered to be corrosive for eyes. Therefore, no local dermal DNELs need to be derived.

 

Long-term toxicity

The key studies for DNEL derivation were identified as a repeated dose oral study according to OECD 422 (de Raaf - Beekhuijzen M.E.W., 2016), where a

NOAEL of 30 mg/kg bw/day was derived and a subchronic inhalation study with multiconstituent aluminium potassium fluoride (Arts J., 2004) in which a NOAEC of 1.21 mg/m3 was derived. The DNELs for chronic systemic toxicity for the dermal route are derived via route-to-route extrapolation based on the repeated dose oral toxicity study. In the absence of substance specific quantitative data on absoption, 100% absorption is assumed for the inhalation and the oral route. For the dermal route, 0.72% absorption is assumed.

Worker DNELs

Acute – inhalation, systemic and local effects

Based on the available sensory irritation study in rats (Muijser H. and J.H.E. Arts, 1999).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 283 mg/m^3	As the acute inhalation toxicity studies (American Biogenics Corporation 1985, WIL Research, 2013) have some limitations regarding the derivation of an acute DNEL, i.e. the lack of a NOAEC from these studies which can be used as starting point, the sensory irritation study with multiconstituent aluminium potassium fluoride (Muijser H. and J.H.E. Arts 1999) is used for the derivation of the acute DNEL. Abnormalities at necropsy consisted primarily of discoloured areas on the lungs to a varying extent at 592 and 604 mg/m3 after 20 and 30 minutes exposure, respectively. Based on these findings, a NOAEC of 283 mg/m3 was derived.
Step 2) Modification of starting point	-                 6.7/10	In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes)’. As the NOAEC concerns 20/30 minutes single exposure no further modification of the starting point is performed.   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).
Step 3) Assessment factors
Interspecies	2.5	For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
Intraspecies	3	Using a reduced factor of 3 (instead of 5) is justified because the critical effect is a local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution, metabolism and elimination play no/a minor role.
Exposure duration	1
Dose response	1
Quality of database	1
Step 4) Calculate DNEL	283 x (6.7/10) / (2.5 x 3 x 1 x 1 x 1) = 25.3 mg/m3

Long-term – inhalation, local effects

Based on 90 days inhalation toxicity study in rats (TNO, 2004)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 1.21 mg/m^3	Presence of macrophages in the lungs was reported for 1.21 and 3.08 mg/m3(not at 0.32 mg/m3). The presence of these macrophages are considered a physiological response to the exposure and therefore not considered adverse as such. The increased lung weights (females) and increased numbers of neutrophils in blood (females) observed at the concentration of 3 mg/m3 are considered adverse. No tissue reaction was present at any of the concentrations tested.
Step 2) Modification of starting point	-       6.7/10	According to the REACH guidance, time scaling is not appropriate when the toxic effect is mainly driven by the exposure concentration. Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).
Step 3) Assessment factors
Interspecies	1	In view of the exaggerated lung reaction of rats to dust inhalation, compared to the reaction of higher mammals (Snipes, 1989, 1996; Nikula et al, 1997, 2001), it is assumed that rats are more sensitive for the effects of aluminium potassium fluoride after inhalation exposure. In rats, significant macrophage activity is accompanied with inflammatory mediator release and inflammatory responses as neutrophils mobilisation (note that in the aluminium potassium fluoride study a tissue reaction was absent). Moreover, considering that retention of particles in higher mammals happens preferentially in the interstitium and considering that aluminium potassium fluoride is moderately (but slowly) soluble it may be assumed that long term retention of aluminium potassium fluoride particles in the interstitium will not occur. Aluminium potassium fluoride will dissociate, dilute and subsequently be transported in the fluids of the organism (Snipes, 1989, 1996; Nikula et al, 1997, 2001). In conclusion, humans are not considered more sensitive compared to rats and mice and an assessment factor of 1 is considered appropriate.
Intraspecies	3	Using a reduced factor of 3 (instead of 5) is justified because the critical effect is a local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution, metabolism and elimination play no/a minor role.
Exposure duration	2	Extrapolation from sub-chronic to chronic exposure
Dose response	1
Quality of database	1
Step 4) Calculate DNEL	(1.21 x 6.7/10) / (1 x 3 x 2 x 1 x 1) = 0.14 mg/m3

 

Long-term dermal, systemic effects

As dermal repeated dose toxicity studies with cesium potassium fluoroaluminate are not available, route to route extrapolation was applied to derive a DNEL for the dermal route, based on the results of a combined 28 -day oral repeated dose toxicity study with reproduction/developmental toxicity screening test performed according to OECD 422 (Charles River, 2016) where a NOAEL of 30 mg/kg bw/day was derived.

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 30 mg/kg bw/day	Exposure of rats at concentrations up to 30 mg/kg bw/day did not induce clinical abnormalities, differences in food consumption and body weight, and changes in haematology or clinical chemistry parameters.Based on the findings in the stomach, kidneys and spleen in the mid and high dose animals, a dose of 30 mg/kg bw/day was considered as NOAEL.
Step 2) Modification of starting point	100/0.72	Conversion into dermal NOAEL (in mg/kg bw/day) assuming 100% oral absorption and 0.72% dermal absorption for cesium potassium fluoroaluminate.
Modified dose-descriptor	30 x (100/1.6) = 4167 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4 x 2.5	Assessment factor for allometric scaling and remaining uncertainties.
Intraspecies	5	Default AF for workers
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study
Dose response	1
Quality of database	1
DNEL	Value
	1875 / (4 x 2.5 x 5 x 6 x 1 x 1) = 13.9 mg/kg bw/day

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation performed

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

extrapolation from sub-acute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

extrapolation rat to human

AF for other interspecies differences:

2.5

Justification:

remaining differences

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

General population DNELs

As there is no consumer use for cesium potassium fluoroaluminate, no inhalation and dermal DNELs for the general population were calculated. However, the deposition of cesium potassium fluoroaluminate in the environment may contribute to the total cesium and fluoride intake of the general public, therefore, a long-term oral DNEL for the general population was calculated. No route-to-route extrapolation had to be performed since the DNEL has been derived from a NOAEL observed in combined 28 -day oral repeated dose toxicity study with reproduction/developmental toxicity screening test performed according to OECD 422 (de Raaf - Beekhuijzen M.E.W., 2016)

Long-term – oral, systemic effects (based on sub-acute oral toxicity study with rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 30 mg/kg bw/day	Exposure of rats at concentrations up to 30 mg/kg bw/day did not induce clinical abnormalities, differences in food consumption and body weight, and changes in haematology or clinical chemistry parameters.Based on changes in clinical biochemistry parameters and the findings in the stomach in the high dose animals, a dose of 30 mg/kg bw/day was considered as NOAEL.
Step 2) Modification of starting point	-
Step 3) Assessment factors
Interspecies	4 x 2.5	Default assessment factors for allometric scaling and remaining interspecies differences.
Intraspecies	10	Default assessment factor for general population
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study.
Dose response	1
Quality of database	1
DNEL	Value
	30 / (4 x 2.5 x 10 x 6 x 1 x 1) = 30 / 600 = 0.05 mg/kg bw/day