Lithium fluoride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor starting point:

NOAEL

Value:

4.48 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

15.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

Performance of the inhalation study was waived according to column 2 REACH Regulation (EC) No 1907/2006, Annex VIII, section 8.6.1 (see IUCLID section 7.5.2).

A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

1

Justification:

Not applicable, since human data are available.

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to "Additional information - worker"

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44.8 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):

1

Dose descriptor starting point:

NOAEL

Value:

4.48 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

44.8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Performance of the dermal study was waived according to column 2 REACH Regulation (EC) No 1907/2006, Annex VIII, section 8.6.1 (see IUCLID section 7.5.3). Based on the physico chemical properties and available study data a 10 % dermal absorption is assumed.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable, since human data are available.

AF for other interspecies differences:

1

Justification:

Not applicable, since human data are available.

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to "Additional information - worker"

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

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:

low hazard (no threshold derived)

Additional information - workers

DNEL derivation for each of the relevant endpoints was based on the most conservative dose descriptors obtained. Assessment factors were assigned accordingly. Thus, the DNELs represent worst-case scenarios. 

Hazard via inhalation route

Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation an inhalation NOAEC was derived by route to route extrapolation (ECHA CSA R.8, 2012). The toxicological relevant component of lithium fluoride is lithium. Thus, the NOAEL long-term oral was calculated to be 4.48 mg LiF/kg bw/day, based on lithium NOAEL long-term oral of 1.2 mg Li/kg bw/day (obtained from human data on long-term (chronic) treatment of bipolar disorder with lithium carbonate, see IUCLID section 7.5). The oral NOAEL long-term (human) of 4.48 mg LiF/kg bw/day was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

 

Step 2: Modification into a correct starting point:

For worker a NOAEC long-term, inhalation was calculated assuming 70 kg per person (70 kg/person x 4.48 mg LiF/kg bw/day = 314 mg/person/day), 8h light activity (10 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes.

 

NOAEC (worker) inhalation = 314 mg LiF/person/day x (1 / 10m³/person/day(8h)) x (50% Abs. / 100 / abs.) = 15.7 mg LiF/m³

 

Step 3: Use of assessment factors: 1

An AF for exposure duration was not applicable, as data covered long-term / chronic exposure. Interspecies AFs were not applicable as the relevant NOAEL was derived from reliable and relevant high quality human data. Intraspecies differences were considered not applicable as the NOAEL was based on therapeutic concentrations (being acceptable to humans, which are physically fit, but also being applicable to all sub-populations, in conclusion being applicable to worker and general population). 

 

The resulting worker DNEL long-term inhalation is 15.7 mg LiF/m³.

 

According to ECHA guidance document CSA R.8, 2012, for dust as in case with lithium fluoride, the general dust limit should be applied if the derived DNEL for inhalation is above the general dust limit (10 mg/m³). The calculated DNEL long-term inhalation for lithium fluoride was determined to be 15.7 mg/m³, the DNEL considered for risk characterisation is the general dust limit of 10 mg/m³.

 

Hazard via dermal route

Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation an inhalation NOAEC was derived by route to route extrapolation (ECHA CSA R.8, 2012). The toxicological relevant component of lithium fluoride is lithium. Thus, the NOAEL long-term oral was calculated to be 4.48 mg LiF/kg bw/day, based on lithium NOAEL long-term oral of 1.2 mg Li/kg bw/day (obtained from human data on long-term (chronic) treatment of bipolar disorder with lithium carbonate, see IUCLID section 7.5). The oral NOAEL long-term (human) of 4.48 mg LiF/kg bw/day was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

 

Step 2: Modification into a correct starting point: 

The NOAEL long-term dermal of 44.8 mg LiF/kg bw/day was calculated from the NOAEL long-term oral of 4.48 mg LiF/kg bw/day considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2017, 7.12). The good water solubility and the low molecular weight support the conclusion that LiF could be absorbed via skin. But dermal penetration is confined by the high hydrophilicity together with the log Pow below 1.The poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Furthermore lithium fluoride consists of a particulate at room temperature, which first has to dissolve into the surface moisture of the skin before systemic uptake can begin. In case of skin contact, these pre-requisites will drastically limit the bioavailable amount of the chemical. The assumption that low or no dermal absorption occurs is strengthened by the results achieved from the dermal toxicity testing with two source substances (LiCl, LiBr).

 

NOAEL long-term dermal = 4.48 mg/kg bw/day x 100%: 10% = 44.8 mg LiF/kg bw/d

 

Step 3: Use of assessment factors: 1

An AF for exposure duration was not applicable, as data covered long-term / chronic exposure. Interspecies AFs were not applicable as the relevant NOAEL was derived from very reliable and relevant high quality human data. Intraspecies differences were considered not applicable as the NOAEL was based on therapeutic concentrations (being acceptable to humans, which are physically fit but also being applicable to all sub-populations) and therefore applicable for worker and general population.

 

The resulting worker DNEL long-term dermal is 44.8 mg LiF/kg bw/d.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.73 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor starting point:

NOAEL

Value:

4.48 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

6.73 mg/m³

Explanation for the modification of the dose descriptor starting point:

Performance of the inhalation study was waived according to column 2 of REACH Regulation (EC) No 1907/2006, Annex VIII, section 8.6.1 (see IUCLID section 7.5.2). A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

1

Justification:

Not applicable, since human data are available.

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to "Additional information - general population"

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44.8 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):

1

Dose descriptor starting point:

NOAEL

Value:

4.48 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

44.8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Performance of the dermal study was waived according to column 2 REACH Regulation (EC) No 1907/2006, Annex VIII, section 8.6.1 (see IUCLID section 7.5.3). Based on the physico chemical properties and available study data a 10 % dermal absorption is assumed.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable, since human data are available.

AF for other interspecies differences:

1

Justification:

Not applicable, since human data are available.

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to "Additional information - general population"

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.48 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):

1

Dose descriptor starting point:

NOAEL

Value:

4.48 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation required.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable, since human data are available.

AF for other interspecies differences:

1

Justification:

Not applicable, since human data are available.

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to "Additional information - general population"

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13.44 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

DNEL derivation for each of the relevant endpoints was based on the most conservative dose descriptors obtained. Assessment factors were assigned accordingly. Thus, the DNELs represent worst-case scenarios. 

 

Hazard via inhalation route

Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation an inhalation NOAEC was derived by route to route extrapolation (ECHA CSA R.8, 2012). The toxicological relevant component of lithium fluoride is lithium. Thus, the NOAEL long-term oral was calculated to be 4.48 mg LiF/kg bw/day, based on lithium NOAEL long-term oral of 1.2 mg Li/kg bw/day (obtained from human data on long-term (chronic) treatment of bipolar disorder with lithium carbonate, see IUCLID section 7.5). The oral NOAEL long-term (human) of 4.48 mg LiF/kg bw/day was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

 

Step 2: Modification into a correct starting point:

For general population a NOAEC long-term, inhalation was calculated assuming 60 kg per person (60 kg/person x 4.48 mg LiF/kg bw/day = 269 mg/person/day), 50 % absorption via oral route and 100 % absorption via inhalatory route and a daily exposure period of 24 hours (corresponding to breathing volume of 20 m³/day).

 

NOAEC (general population) inhalation = 269 mg LiF/person/day * (1 / 20 m³/person/day(24h)) * (50 % Abs./ 100 % Abs.)= 6.73 mg LiF/m³

 

Step 3: Use of assessment factors: 1

An AF for exposure duration was not applicable, as data covered long-term / chronic exposure. Interspecies AFs were not applicable as the relevant NOAEL was derived from reliable and relevant high quality human data. Intraspecies differences were considered not applicable as the NOAEL was based on therapeutic concentrations (being acceptable to humans, which are physically fit but also being applicable to all sub-populations), being applicable for general population.

The resulting general population DNEL long-term inhalation is 6.73 mg LiF/m³/day.

 

Hazard via dermal route

Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation an inhalation NOAEC was derived by route to route extrapolation (ECHA CSA R.8, 2012). The toxicological relevant component of lithium fluoride is lithium. Thus, the NOAEL long-term oral was calculated to be 4.48 mg LiF/kg bw/day, based on lithium NOAEL long-term oral of 1.2 mg Li/kg bw/day (obtained from human data on long-term (chronic) treatment of bipolar disorder with lithium carbonate, see IUCLID section 7.5). The oral NOAEL long-term (human) of 4.48 mg LiF/kg bw/day was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

Step 2: Modification into a correct starting point: 

The NOAEL long-term dermal of 44.8 mg LiF/kg bw/day was calculated from the NOAEL long-term oral of 4.48 mg LiF/kg bw/day based on lithium NOAEL long-term oral of 1.2 mg Li/kg bw/day (obtained from human data on long-term (chronic) treatment of bipolar disorder with lithium carbonate, see IUCLID section 7.5). A conservative 10 % absorption through the skin (ECHA document R.7C, 2017, 7.12) was considered. The good water solubility and the low molecular weight support the conclusion that LiF could be absorbed via skin. But dermal penetration is confined by the high hydrophilicity together with the log Pow below 1.The poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Furthermore lithium fluoride consists of a particulate at room temperature, which first has to dissolve into the surface moisture of the skin before systemic uptake can begin. These pre-requisites will drastically limit the bioavailable amount of the chemical when in contact to skin. The assumption that low or no dermal absorption occurs is strengthened by the results achieved from the dermal toxicity testing with two source substances (LiCl, LiBr). 

 

NOAEL long-term dermal = 4.48 mg/kg bw/day x 100%: 10% = 44.8 mg LiF/kg bw/day

 

Step 3: Use of assessment factors: 1

An AF for exposure duration was not applicable, as data covered long-term / chronic exposure. Interspecies AFs were not applicable as the relevant NOAEL was derived from very reliable and relevant high quality human data. Intraspecies differences were considered not applicable as the NOAEL was based on therapeutic concentrations being also acceptable to general population.

The resulting general population DNEL long-term dermal is 44.8 mg LiF/kg bw/day.

 

Hazard via oral route

Step 1: Selection of the relevant dose descriptor (starting point):

The toxicological relevant component of lithium fluoride is lithium. Thus, the NOAEL long-term oral was calculated to be 4.48 mg LiF/kg bw/day, based on lithium NOAEL long-term oral of 1.2 mg Li/kg bw/day (obtained from human data on long-term (chronic) treatment of bipolar disorder with lithium carbonate, see IUCLID section 7.5). The oral NOAEL long-term (human) of 4.48 mg LiF/kg bw/day was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

Step 2: Modification into a correct starting point: 

Not required.

 

Step 3: Use of assessment factors: 1

An AF for exposure duration was not applicable as the available data covered long-term / chronic exposure. Interspecies AFs were not applicable as the relevant NOAEL was derived from reliable and relevant high quality human data. Intraspecies differences were considered not applicable as the NOAEL was based on therapeutic concentrations being applicable to general population. The resulting DNEL general population long-term oral is 4.48 mg LiF/kg bw/day.