Potassium tetrafluoroaluminate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

22.4 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

7.5

Modified dose descriptor starting point:

NOAEC

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.12 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

6

Dose descriptor:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

22.4 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

7.5

Dose descriptor starting point:

NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

189 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

DNEL related information

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

Based on the current data available regarding exposure, one main type of exposure occurs in case of potassium tetrafluoroaluminate: exposure to potassium tetrafluoroaluminate dust. Furthermore, in some scenarios (see table) processes occur under high temperatures which results in hydrogen fluoride exposure (partly as a result of potassium tetrafluoroaluminate use). 

Short description of Identified Use

ES1: Manufacturing of potassium tetrafluoroaluminate

Synthetic potassium tetrafluoroaluminate production (hot melt process)

ES3: End use as brazing and soldering flux of potassium tetrafluoroaluminate

Brazing and soldering end use of potassium tetrafluoroaluminate

ES4: End use as other flux of potassium tetrafluoroaluminate

Use as flux in the Aluminium and Steel industry

Use of tablets in Aluminium smelting

ES5: Production of articles containing potassium tetrafluoroaluminate

Tile production in ovens

Production of glassware (as opalising agents)

ES6: End use of articles containing potassium tetrafluoroaluminate in industry

Use of cutting and grinding applications, e.g. the use of grinding wheels, cutting disks.

Welding, indoor, open processing

Welding, indoor, closed processing

ES7: End use of articles containing potassium tetrafluoroaluminate by professionals

Use of cutting and grinding applications, e.g. the use of grinding wheels, cutting disks, indoor

Welding, indoor, open processing

ES8: End use of articles containing potassium tetrafluoroaluminate by consumers

Use in cutting and grinding applications, e.g. the use of grinding wheels, cutting disks.

Welding, indoor, open processing

 

Regarding selection of the critical DNELs, it is noted that according to the REACH regulation ‘DNELs’ already derived for the substance under consideration by the EU (see EU-RARs) or by the SCOEL should be considered.

 

In Annex I of REACH, section 0.5, it is explicitly mentioned that:

“….. Where available and appropriate, an assessment carried out under Community legislation (e.g. risk assessments completed under Regulation (EEC) No 793/93) shall be taken into account in the development of, and reflected in, the chemical safety report. Deviations from such assessments shall be justified”.

 

In Appendix R.8-13 of the Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health it is noted that:

‘When an EU IOEL exists the registrant may, under conditions as described below, use the IOEL in place of developing a DNEL. A registrant is allowed to use an IOEL as a DNEL for the same exposure route and duration, unless new scientific information that he has obtained in fulfilling his obligations under REACH does not support the use of the IOEL for this purpose. This could be because the information obtained is more recent than the information that was used to support setting the IOEL at EU level and because it leads to another value being derived which requires different risk management measures (RMMs) and operational conditions (OCs)’.

 

Therefore, the SCOEL evaluation of hydrogen fluoride and the CSR of hydrogen fluoride were also considered.

Summary Table of worker DNELs

 

Acute inhalation DNEL

Exposure pattern	Method	Exposure form	Critical effect	DNEL	Remarks
Acute inhalation (DNEL for 15 minutes exposure)	REACH guidance	potassium tetrafluoroaluminate	alveolar congestion / haemorrhage	22.4 mg/m^3	-
	SCOEL recommendation hydrogen fluoride / CSR of hydrogen fluoride	hydrogen fluoride	irritation	2.5 mg/m^3	STEL of the SCOEL for hydrogen fluoride.Based upon the study of Largent and Columbus (1960), conducted in volunteers exposed for 6 h/d for 10-50d, a STEL (15 mins) of 3 ppm (2.5 mg/m^3) was proposed for hydrogen fluoride to limit peaks in exposure which could result in irritation.

 

For short term exposure to potassium tetrafluoroaluminate dust, a DNEL is derived according to the REACH guidance. Assessment of short term exposure is not considered relevant, when 8 hour exposure levels maintain under the chronic-DNEL. The short term DNEL for potassium tetrafluoroaluminate dust is very high (22.4 mg/m³, about 185 times higher) relative to the chronic DNEL for potassium tetrafluoroaluminate dust.

The relationship between determinants of acute and full shift exposure distributions have been calculated (Kumagai and Matsunaga, 1994). In general, the 95^thpercentile of 15 minute exposure data is about twice the 90^thpercentile and 4 times the 75^thpercentile of full shift data collected for the same situation. Even in a worst case situation when:

- the full shift measurement data reflects the 75^thpercentile,

- there is a high variability within the short term data,

- the 99^thpercentile of the short term value is required,

the factor by which to multiply the 8 hour value to get to the short term value is 40.

This is still much lower than 185. This means that when 8 hour exposures remain under the chronic DNEL for potassium tetrafluoroaluminate, the 15 minute exposure levels will always be safe. Therefore, no quantitative risk characterisation for short-term exposure will be performed for workers.

 

Remark:

Exposure to hydrogen fluoride may occur in some scenarios. The hydrogen fluoride exposure is in part a result of potassium tetrafluoroaluminate present. The acute DNEL for hydrogen fluoride is 2.5 mg/m³. For a quantitative risk characterisation for hydrogen fluoride it is referred to the CSR of hydrogen fluoride.

 

Long-term inhalation DNEL

Exposure pattern	Method	Exposure form	Critical effect	DNEL	Remarks
Long-term inhalation (DNEL for 8 hours exposure)	REACH guidance	potassium tetrafluoroaluminate	local effects in the respiratory tract	0.12 mg/m^3	-
	SCOEL recommendation hydrogen fluoride / CSR of hydrogen fluoride	hydrogen fluoride	skeletal fluorosis	1.5 mg/m^3	8-hour TWA SCOEL for hydrogen fluoride of 1.5 mg/m^3is proposed as DNEL in the CSR of hydrogen fluoride.

 

Remark:

Exposure to hydrogen fluoride may occur in some scenarios. The hydrogen fluoride exposure is in part a result of potassium tetrafluoroaluminate present. The long-term inhalation DNEL for hydrogen fluoride is 1.5 mg/m³. For a quantitative risk characterisation for hydrogen fluoride it is referred to the CSR of hydrogen fluoride.

 

Long-term dermal DNEL

Exposure pattern	Method	Exposure form	Critical effect	DNEL	Remarks
Long-term dermal (DNEL for daily exposure)	REACH guidance	potassium tetrafluoroaluminate	developmental toxic effects	189 mg/kg bw/day	route-to-route extrapolation using oral data as starting point
	CSR of hydrogen fluoride	hydrogen fluoride	skeletal fluorosis	not quantifiable due to lack of dermal absorption

 

Detailed presentation of worker DNEL derivation

Acute – inhalation, systemic and local effects

Approach according to REACH guidance

Based on the available acute inhalation toxicity study in rats with the read-across candidate multiconstituent aluminium potassium fluoride (TNO, 1999b).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 283 mg/m^3x 142/160 = 251 mg/m^3	As the acute inhalation toxicity studies (American Biogenics Corporation, 1985a, b) 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 (TNO, 1999b) with the multiconstituent aluminium potassium fluoride 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/m^3after 20 and 30 minutes exposure, respectively. Based on these findings, a NOAEC of 283 mg/m^3was derived for the multiconstituent aluminium potassium fluoride.   Application of read-across: The main difference between potassium tetrafluoroaluminate and multiconstituent aluminium potassium fluoride lies in the fact that potassium tetrafluoroaluminate is a monoconstituent substance (the concentration of the main constituent potassium tetrafluoroaluminate is ≥90%), while multiconstituent aluminium potassium fluoride is a multiconstituent substance, containing ca. 70% of KAlF4 and ca. 30% of the salts of higher homological penta- and hexafluoroaluminic acids K2AlF5 and K3AlF6. The presence of these higher homological salts is, however, not expected to alter significantly the physico-chemical and toxicological properties of multiconstituent aluminium potassium fluoride in comparison to potassium tetrafluoroaluminate. Only a correction for molecular weight (160 g/mol for multiconstituent aluminium potassium fluoride vs. 142 g/mol for potassium tetrafluoroaluminate) is applied.
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 m^3/10 m^3).
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	(251 x 6.7/10) / (2.5 x 3 x 1 x 1 x 1) = 22.4 mg/m^3

Long-term – inhalation, local effects

Approach according to REACH guidance

Based on 90 days inhalation toxicity study with the read-across candidate multiconstituent aluminium potassium fluoride in rats (TNO, 2004b)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 1.21 mg/m^3x 142/160 = 1.07 mg/m^3	Presence of macrophages in the lungs was reported for 1.21 and 3.08 mg/m^3(not at 0.32 mg/m^3) in the 90-day study with the multiconstituent aluminium potassium fluoride. The presence of these macrophages is 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 3.08 mg/m^3are considered adverse. No tissue reaction was present at any of the concentrations tested.   Application of read-across: The main difference between potassium tetrafluoroaluminate and multiconstituent aluminium potassium fluoride lies in the fact that potassium tetrafluoroaluminate is a monoconstituent substance (the concentration of the main constituent KAlF4 is ≥90%), while multiconstituent aluminium potassium fluoride is a multiconstituent substance, containing ca. 70% of KAlF4 and ca. 30% of the salts of higher homological penta- and hexafluoroaluminic acids K2AlF5 and K3AlF6. The presence of these higher homological salts is, however, not expected to alter significantly the physico-chemical and toxicological properties of multiconstituent aluminium potassium fluoride in comparison to potassium tetrafluoroaluminate. Only a correction for molecular weight (160 g/mol for multiconstituent aluminium potassium fluoride vs. 142 g/mol for potassium tetrafluoroaluminate) is applied.
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 m^3/10 m^3).
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, 1996, Nikula et al, 1997, 2001), it is assumed that rats are more sensitive for the effects of multiconstituent 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 multiconstituent 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 multiconstituent aluminium potassium fluoride is moderately (but slowly) soluble, it may be assumed that long term retention of multiconstituent aluminium potassium fluoride particles in the interstitium will not occur. Multiconstituent aluminium potassium fluoride will dissociate, dilute and subsequently be transported in the fluids of the organism (Snipes, 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	(1.07 x 6.7/10) / (1 x 3 x 2 x 1 x 1) = 0.12 mg/m^3

- Nikula KJ,KJ, Griffith WC, Mauderly JL (1997).Lung tissue responses and sites of particle retention differ between rats and cynomolgus monkeys exposed chronically to diesel exhaust and coal dust.Fundam Appl Toxicol.;37(1):37-53.

- Nikula KJ, Vallyathan V, Green FH, Hahn FF (2001).Influence of exposure concentration or dose on the distribution of particulate material in rat and human lungs.Environ Health Perspect.;109(4):311-8.

- Snipes MB (1989).Long-term retention and clearance of particles inhaled by mammalian species.Crit Rev Toxicol.;20(3):175-211.

- Snipes MB (1996). Current information on lung overload in nonrodent mammals: Contrast with rats. Inhal. Toxicol. 8:91-109.

Long-term – dermal, systemic effects

Approach according to REACH guidance

No dermal repeated dose toxicity studies are available for potassium tetrafluoroaluminate. In the inhalation repeated dose toxicity studies with a read-across candidate multiconstituent aluminium potassium fluoride no systemic effects were observed. Therefore a dermal long-term DNEL cannot be quantified using the inhalation route as starting point.

For the structural analogue of potassium tetrafluoroaluminate, cryolite, effects on postnatal growth evidenced by significantly decreased pup body weights during lactation as well as pathologic gross findings in several organs of the pups resulted from dose levels without any significant parental toxicity in the two-generation study (oral route) (Pharmaco LSR, Inc., 1994). Because these effects occurred without any significant sign for parental toxicity it is considered to be indicative for a specific toxic potential of cryolite adverse to postnatal development. The respective NOAEL for these effects in this study was 42 mg cryolite/kg bw/day. This level will be used for derivation of the dermal DNEL of potassium tetrafluoroaluminate.

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 42 mg/kg bw/day x 142/210 = 28.4 mg/kg bw/day	Read-across using the two-generation study of the structural analogue cryolite: NOAEL for developmental toxic effects is 42 mg/kg bw/day.   Application of read-across: Reproduction toxicity concerns a systemic effect, which is expected to be primarily governed by the presence of fluoride anions formed upon dissociation of fluoroaluminate moieties. The contents of fluoride, expressed as a percentage of molar weight, are almost identical for potassium tetrafluoroaluminate and cryolite. Therefore it is considered acceptable to derive the lacking data on potassium tetrafluoroaluminate by read-across from cryolite. Only a correction for molecular weight (210 g/mol for cryolite vs. 142 g for potassium tetrafluoroaluminate) is applied.
Step 2) Modification of starting point	100 / 0.3	Conversion into dermal NAEL (in mg/kg bw/day) assuming 100% oral absorption and 0.3% dermal absorption for potassium tetrafluoroaluminate.
Step 3) Assessment factors
Interspecies	4 x 2.5	Default assessment factor for allometric scaling and remaining uncertainties as taken from the REACH guidance.
Intraspecies	5	Default assessment factor for workers taken from REACH.
Exposure duration	1	Not applicable
Dose response	1
Quality of database	1
Step 4) Calculate DNEL	(28.4 x 100/0.3) /(4 x 2.5 x 5 x 1 x 1 x 1) = 189 mg/kg bw/day

 

No data are available concerning local effects after repeated dermal contact with potassium tetrafluoroaluminate. The acute skin tests with multiconstituent aluminium potassium fluoride did not show local irritating or sensitising properties. From epidemiological data no observations on skin reactions from workers have been reported. In summary local effects by prolonged skin contact are not expected.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.7 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

15

Modified dose descriptor starting point:

NOAEC

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.02 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

12

Dose descriptor:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.7 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

15

Dose descriptor starting point:

NOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

33.4 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - General Population

Summary Table of general population DNELs

 

Acute inhalation DNEL

Exposure pattern	Method	Exposure form	Critical effect	DNEL	Remarks
Acute inhalation (DNEL for 15 minutes exposure)	REACH guidance	potassium tetrafluoroaluminate	alveolar congestion / haemorrhage	16.7 mg/m^3	-
	CSR of hydrogen fluoride	hydrogen fluoride	irritation	1.25 mg/m^3	The EU IOEL value of 2.5 mg/m^3(3 ppm) was derived based on the results of the volunteer study of Largent & Columbus (1960) to limit peaks in exposure which could result in irritation. The application of an additional assessment factor of 2 (representing the potential for greater sensitivity of individuals within the general population and consistent with REACH guidance) to take into account potential additional intra-species variation in the exposed general population is considered to be appropriate.

 

For short term exposure to potassium tetrafluoroaluminate dust, a DNEL is derived according to the REACH guidance. Assessment of short term exposure is not considered relevant, when 24 hour exposure levels maintain under the chronic-DNEL. The short term DNEL for potassium tetrafluoroaluminate is very high (16.7 mg/m³,more than 800 times higher) relative to the chronic DNEL for potassium tetrafluoroaluminate dust (0.02 mg/m³). If the 24 hour exposure remains under 0.02 mg/m², it is mathematically not possible to have a 15 minute exposure level above 1.92 mg/m³. The 15 minute exposure levels will always be safe. Therefore, no quantitative risk characterisation for short-term exposure will be performed for the general population.

Remark:

Exposure to hydrogen fluoride may occur in some scenarios. The hydrogen fluoride exposure is in part a result of potassium tetrafluoroaluminate present. The acute DNEL for hydrogen fluoride is 1.25 mg/m³. For a quantitative risk characterisation for hydrogen fluoride it is referred to the CSR of hydrogen fluoride.

 

Long-term inhalation DNEL

Exposure pattern	Method	Exposure form	Critical effect	DNEL	Remarks
Long-term inhalation (DNEL for 24 hours exposure)	REACH guidance	potassium tetrafluoroaluminate	local effects in the respiratory tract	0.02 mg/m^3	-
	CSR of hydrogen fluoride	hydrogen fluoride	skeletal fluorosis	0.03 mg/m^3	-

 

Remark:

Exposure to hydrogen fluoride may occur in some scenarios. The hydrogen fluoride exposure is in part a result of potassium tetrafluoroaluminate present. The long-term inhalation DNEL for hydrogen fluoride is 0.03 mg/m³. For a quantitative risk characterisation for hydrogen fluoride it is referred to the CSR of hydrogen fluoride.

 

Long-term dermal DNEL

Exposure pattern	Method	Exposure form	Critical effect	DNEL	Remarks
Long-term dermal (DNEL for daily exposure)	REACH guidance	potassium tetrafluoroaluminate	developmental toxic effects	33.4 mg/kg bw/day	route-to-route extrapolation using oral data as starting point
	CSR of hydrogen fluoride	hydrogen fluoride	skeletal fluorosis	not quantifiable due to lack of dermal absorption

 

Detailed presentation of general population DNEL derivation

Acute – inhalation, systemic and local effects

Approach according to REACH guidance

Based on the available acute inhalation toxicity study in rats (TNO, 1999b) with the read-across candidate multiconstituent aluminium potassium fluoride.

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 283 mg/m^3x 142/160 = 251 mg/m^3	As the acute inhalation toxicity studies (American Biogenics Corporation, 1985a, b) 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 (TNO, 1999b) with the multiconstituent aluminium potassium fluoride 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/m^3after 20 and 30 minutes exposure, respectively. Based on these findings, a NOAEC of 283 mg/m^3was derived for the multiconstituent aluminium potassium fluoride.   Application of read-across: The main difference between potassium tetrafluoroaluminate and multiconstituent aluminium potassium fluoride lies in the fact that potassium tetrafluoroaluminate is a monoconstituent substance (the concentration of the main constituent KAlF4is ≥90%), while multiconstituent aluminium potassium fluoride is a multiconstituent substance, containing ca. 70% of KAlF4 and ca. 30% of the salts of higher homological penta- and hexafluoroaluminic acids K2AlF5 and K3AlF6. The presence of these higher homological salts is, however, not expected to alter significantly the physico-chemical and toxicological properties of multiconstituent aluminium potassium fluoride in comparison to potassium tetrafluoroaluminate. Only a correction for molecular weight (160 g/mol for multiconstituent aluminium potassium fluoride vs. 142 g/mol for potassium tetrafluoroaluminate) is applied.
Step 2) Modification of starting point	-	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.
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	6	Using a reduced factor 6 (instead of 10) is justified because the critical effect is a direct local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution and elimination play no/a minor role.
Exposure duration	1
Dose response	1
Quality of database	1
Step 4) Calculate DNEL	251 / (2.5 x 6 x 1 x 1 x 1) = 16.7 mg/m^3

Long-term – inhalation, local effects

Approach according to REACH guidance

Based on 90 days inhalation toxicity study in rats (TNO, 2004b) with the read-across candidate multiconstituent aluminium potassium fluoride

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 1.21 mg/m^3x 142/160 = 1.07 mg/m^3	Presence of macrophages in the lungs was reported for 1.21 and 3.08 mg/m^3(not at 0.32 mg/m^3) in the 90-day study with the multiconstituent aluminium potassium fluoride. The presence of these macrophages is 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 3.08 mg/m^3are considered adverse. No tissue reaction was present at any of the concentrations tested.   Application of read-across: The main difference between potassium tetrafluoroaluminate and multiconstituent aluminium potassium fluoride lies in the fact that potassium tetrafluoroaluminate is a monoconstituent substance (the concentration of the main constituent KAlF4 is 90%), while multiconstituent aluminium potassium fluorideis a multiconstituent substance, containing ca. 70% of KAlF4 and ca. 30% of the salts of higher homological penta- and hexafluoroaluminic acids K2AlF5 and K3AlF6. The presence of these higher homological salts is, however, not expected to alter significantly the physico-chemical and toxicological properties of multiconstituent aluminium potassium fluoridein comparison to potassium tetrafluoroaluminate. Only a correction for molecular weight (160 g/mol for multiconstituent aluminium potassium fluoride vs. 142 g/mol for potassium tetrafluoroaluminate) is applied.
Step 2) Modification of starting point	6/24	Correction of exposure duration in study (6 hrs/day) to default population exposure (24 hrs/day).
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 the multiconstituent 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 multiconstituent 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 the multiconstituent aluminium potassium fluoride is moderately (but slowly) soluble, it may be assumed that long term retention of multiconstituent aluminium potassium fluoride particles in the interstitium will not occur. Multiconstituent 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	6	Using a reduced factor 6 (instead of 10) is justified because the critical effect is a direct local effect that is hardly if at all, mainly determined by toxicodynamics and kinetics. Absorption, distribution 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	(1.07 x 6/24) / (1 x 6 x 2 x 1 x 1) = 0.02 mg/m^3

- Nikula KJ,KJ, Griffith WC, Mauderly JL (1997).Lung tissue responses and sites of particle retention differ between rats and cynomolgus monkeys exposed chronically to diesel exhaust and coal dust.Fundam Appl Toxicol.;37(1):37-53.

- Nikula KJ, Vallyathan V, Green FH, Hahn FF (2001).Influence of exposure concentration or dose on the distribution of particulate material in rat and human lungs.Environ Health Perspect.;109(4):311-8.

- Snipes MB (1989).Long-term retention and clearance of particles inhaled by mammalian species.Crit Rev Toxicol.;20(3):175-211.

- Snipes MB (1996). Current information on lung overload in nonrodent mammals: Contrast with rats. Inhal. Toxicol. 8:91-109.

Long-term – dermal, systemic effects

Approach according to REACH guidance

No dermal repeated dose toxicity studies are available for potassium tetrafluoroaluminate. In the inhalation repeated dose toxicity studies no systemic effects were observed. Therefore a dermal long-term DNEL cannot be quantified using the inhalation route as starting point.

For the structural analogue of potassium tetrafluoroaluminate, cryolite,effects on postnatal growth evidenced by significantly decreased pup body weights during lactation as well as pathologic gross findings in several organs of the pups resulted from dose levels without any significant parental toxicity in the two-generation study (oral route) (Pharmaco LSR, Inc., 1994). Because these effects occurred without any significant sign for parental toxicity it is considered to be indicative for a specific toxic potential of cryolite adverse to postnatal development. The respective NOAEL for these effects in this study was 42 mg cryolite/kg bw/day. This level will be used for derivation of the dermal DNEL of potassium tetrafluoroaluminate.

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 42 mg/kg bw/day x 142/210 = 28.4 mg/kg bw/day	Read-across using the two-generation study of the structural analogue cryolite: developmental toxic effects were observed at the dose level of 128 mg/kg bw/day and higher.   Application of read-across: Reproduction toxicity concerns a systemic effect, which is expected to be primarily governed by the presence of fluoride anions formed upon dissociation of fluoroaluminate moieties. The contents of fluoride, expressed as a percentage of molar weight, are almost identical for potassium tetrafluoroaluminate and cryolite. Therefore it is considered acceptable to derive the lacking data on potassium tetrafluoroaluminate by read-across from cryolite. Only a correction for molecular weight (210 g/mol for cryolite vs. 142 g for potassium tetrafluoroaluminate) is applied.
Step 2) Modification of starting point	100 / 0.85	Conversion into dermal NAEL (in mg/kg bw/day) assuming 100% oral absorption and 0.85% dermal absorption for potassium tetrafluoroaluminate.
Step 3) Assessment factors
Interspecies	4 x 2.5	Default assessment factor for allometric scaling and remaining uncertainties as taken from the REACH guidance.
Intraspecies	10	Default assessment factor taken from REACH.
Exposure duration	1	Not applicable
Dose response	1
Quality of database	1
Step 4) Calculate DNEL	(28.4 x 100/0.85) / (4 x 2.5 x 10 x 1 x 1 x 1) = 33.4 mg/kg bw/day

No data are available concerning local effects after repeated dermal contact with potassium tetrafluoroaluminate. The acute skin tests with multiconstituent aluminium potassium fluoride did not show local irritating or sensitising properties. From epidemiological data no observations on skin reactions have been reported. In summary local effects by prolonged skin contact are not expected.