Lithium acetate

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:

11.41 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

39.94 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:

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

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:

114.1 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:

11.41 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

114.1 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 of REACH Regulation (EC) No 1907/2006, Annex VIII, section 8.6.1 (see IUCLID section 7.5.3). 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:

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

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

General:

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. 

Worker – 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 Guidance on information requirements and chemical safety assessment Chapter R.8, 2012). The oral NOAEL long-term (human) of 11.41 mg Li acetate/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 NOEC long-term, inhalation was calculated assuming 70 kg per person (70 kg/person x 11.41 mg Li acetate/kg bw/day = 798.7 mg/person/day), 8h light activity (10 m³ breathing volume), 100 % absorption via oral route and 100 % absorption via inhalatory route.

 

NOAEC (worker) inhalation = 798.7 mg Li acetate/person/day * (1 / 10 m³/person/day(8h)) * (50% Abs. /100 / abs.) = 39.94 mg/m³ (anhydrous) = 61.74 mg/m³ (dihydrate)

  

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 39.94 mg/m³ (39.94 mg/m³ : 1 (AFs)) for lithium acetate, corresponding to 61.74 mg/m³ for lithium acetate dihydrate. According to ECHA guidance on information requirement and chemical safety assessment, Chapter R.8, 2012, for dust as in case with lithium acetate, 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 acetate was determined to be 39.94 mg/m³ (corresponding to 61.74 mg/m³ for lithium acetate dihydrate), the DNEL considered for risk characterisation is the general dust limit of 10 mg/m³.

Worker – 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 Guidance on information requirement and chemical safety assessment Chapter R.8, 2012). The oral NOAEL long-term (human) of 11.41 mg Li acetate/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 114.1 mg Li acetate/kg bw/day was calculated from the NOAEL long-term oral of 11.41 mg Li acetate/kg bw/day considering a conservative 10 % absorption through the skin (ECHA Guidance on information requirement and chemical safety assessment, Chapter R.7C, 2017).

 

NOAEL (Li acetate) long-term dermal = 11.41 mg/kg bw/day x 100%: 10% = 114.1 mg CH3COOLi/kg bw/day = 176.4 mg CH3COOLi*2H2O/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 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 114.1 mg/kg bw/day for lithium acetate (114.1 mg/kg bw/day: 1 (AFs) = 114.1 mg Li acetate/kg bw/day), corresponding to 176.4 mg/kg bw/day for lithium acetate dihydrate.  

General Population - 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:

11.41 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

17.12 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:

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:

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:

114.1 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:

11.41 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

114.1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Calculations based on worst case. Performance of the study was waived according to column 2 REACH Regulation (EC) No 1907/2006 VIII, section 8.6.1 (see IUCLID section 7.5.3).

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

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:

11.41 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:

11.41 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

11.41 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 popupaltion"

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:

34.23 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

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

Gerneral:

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.

 

General population – 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 Guidance on information requirements and chemical safety assessment, Chapter R.8, 2012). The oral NOAEL long-term (human) of 11.41 mg Li acetate/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 NOEC long-term, inhalation was calculated assuming 60 kg per person (60 kg/person x 11.41 mg Li acetate/kg bw/day = 684.6 mg/person/day), 50 % absorption via oral routes and 100 % absorption via inhalatory routes and a daily exposure period of 24 hours (corresponding to breathing volume of 20 m³/day).

 

NOAEC (general population) inhalation = 684.6 mg Li acetate/person/day * (1 / 20 m³/person/ day(24h)) *(50 % Abs./ 100 % Abs.)= 17.12 mg CH3COOLi/m³ = 26.46 mg CH3COOLi*2H2O/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 17.12 mg/m³/day (17.12 mg/m³/day : 1 (AFs)) for lithium acetate, corresponding to 26.46 mg/m³/day for lithium acetate dihydrate. According to ECHA guidance document CSA R.8, 2012, for dust as in case with lithium acetate, 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 acetate was determined to be 17.12 mg/m³ (corresponding to 26.46 mg/m³ for lithium acetate dihydrate), the DNEL considered for risk characterisation is the general dust limit of 10 mg/m³.

  

General population – Hazard via dermal route

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

For risk characterisation a dermal NOAEL was derived by route to route extrapolation. The oral NOAEL of 11.41 mg Li acetate/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 114.1 mg Li acetate/kg bw/day was calculated from the NOAEL long-term oral of 11.41 mg Li acetate/kg bw/day considering a conservative 10 % absorption through the skin (ECHA Guidance on information requirements and chemical safety assessment, Chapter R.7C, June 2017).

 

NOAEL (Li acetate) long-term dermal = 11.41 mg/kg bw/day x 100%: 10% = 114.1 mg CH3COOLi/kg bw/day = 176.4 mg CH3COOLi*2H2O/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 114.1 mg/kg bw/day for lithium acetate (114.1 mg/kg bw/day: 1 (AFs) = 114.1 mg Li acetate/kg bw/day), corresponding to 176.4 mg/kg bw/day for lithium acetate dihydrate.

 

General population - Hazard via oral route

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

The toxicological relevant component of lithium acetate is lithium. Thus, the NOAEL long-term oral was calculated to be 11.41 mg/kg bw/day for lithium acetate, 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).

 

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 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 11.41 mg/kg bw/day for lithium acetate (11.41 mg Li acetate/kg bw/day : 1 (AFs)), corresponding to 17.64 mg/kg bw/day for lithium acetate dihydrate.