Lithium sulphate

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

Modified dose descriptor starting point:

NOAEC

Value:

33.26 mg/m³

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 of REACH Regulation (EC) No 1907/2006, Annex VIII, section 8.6.1 (see IUCLID section 7.5.2).

AF for dose response relationship:

1

Justification:

NOAEL (human, oral) value was initially used for calculations

AF for differences in duration of exposure:

1

Justification:

Recommended AF (for chronic exposure) ECHA REACH Guidance document R8, 2012

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable according to ECHA REACH Guidance document R8, 2012

AF for other interspecies differences:

1

Justification:

Not applicable, derived from human data

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to the discussion

AF for the quality of the whole database:

1

Justification:

Please refer to the discussion

AF for remaining uncertainties:

1

Justification:

Please refer to the discussion

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

95 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

Modified dose descriptor starting point:

NOAEL

Value:

95 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 of REACH Regulation (EC) No 1907/2006, Annex VIII, section 8.6.1 (see IUCLID section 7.5.2).

AF for dose response relationship:

1

Justification:

NOAEL (human, oral) value used for calculations

AF for differences in duration of exposure:

1

Justification:

Recommended AF (for chronic exposure) ECHA REACH Guidance document R8, 2012

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable, derived from human data

AF for other interspecies differences:

1

Justification:

Not applicable, derived from human data

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to the discussion

AF for the quality of the whole database:

1

Justification:

Please refer to the discussion

AF for remaining uncertainties:

1

Justification:

Please refer to the discussion

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

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.

DNEL long-term inhalation, systemic

According to ECHA guidance document CSA: R8, 2012, for dust as in the case with lithium sulfate and lithium sulfate monohydrate, the general dust limit should be applied if the derived DNEL for inhalation is above the general dust limit (10 mg/m³).

As the calculated DNEL long-term inhalation for lithium sulfate and lithium sulfate monohydrate was determined to be 33.27 mg/m³ and 38.72 mg/m³, respectively (see below *), the DNEL considered for risk characterisation is the general dust limit of 10 mg/m³.

* An inhalation NOAEC was derived by route-to-route extrapolation (ECHA CSR R8, 2012) from the lithium NOAEL long-term oral (human) value of 1.2 mg Li/kg bw/day, corresponding to 84 mg Li/person/day (70 kg/person x 1.2 mg Li/kg bw/day), as lithium is the toxicological relevant component of lithium sulfate (obtained from human data, long-term (chronic) treatment of bipolar disorder with lithium carbonate, see IUCLID section 7.5). The oral, long-term (human) NOAEL of 1.2 mg Li/kg bw/day was converted to an inhalation NOAEC (human), assuming, 70 kg body weight for worker, 100 % absorption via the lung, 50 % absorption via the oral route and a daily exposure period of 8 hours during light activity (corresponding to breathing volume of 10 m³/day). Accordingly, a NOAEC of 4.2 mg Li/m³ equivalent to 33.26 mg Li2SO4/m³ and 38.71 mg Li2SO4*H2O/m³ was calculated.

NOAEC (worker) inhalation = 84 mg Li/person/ day * (1 / 10m³/person/day(8h)) * (50 % Abs. / 100 % abs.) = 4.2 mg Li/m³

= 33.26 mg Li2SO4/m³

= 38.71 mg Li2SO4*H2O/m³.

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 33.26 mg Li2SO4/m³/day and 38.71 mg Li2SO4*H2O/m³/day

(33.26 mg/m³/day : 1 (AFs); 38.71 mg/m³/day : 1 (AFs)).

DNEL long-term dermal, systemic

The NOAEL long-term dermal of 95.0 mg Li2SO4/kg bw/day and 110.6 mg Li2SO4*H2O/kg bw/day were calculated from the NOAEL long-term oral of 9.50 mg Li2SO4/kg bw/day and 11.06 mg Li2SO4*H2O/kg bw/day considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2012, 7.12).

NOAEL (Li2SO4) long-term dermal = 9.5 mg/kg bw/day x 100% : 10% = 95 mg Li2SO4/kg bw/day;

NOAEL (Li2SO4*H2O) long-term dermal = 11.06 mg/kg bw/day x 100% : 10% = 110.6 mg Li2SO4*H2O/kg bw/day.

The NOAEL long-term oral and thus the NOAEL long-term dermal are based on lithium toxicity as lithium is the toxicological relevant component of lithium sulfate. 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

DNEL long-term dermal (Li2SO4) is 95.0 mg Li2SO4/kg bw/day : 1 (AFs) = 95.0 mg Li2SO4/kg bw/day and

DNEL long-term dermal (Li2SO4*H2O) is 110.6 mg Li2SO4*H2O/kg bw/day : 1 (AFs) = 110.6 mg Li2SO4*H2O/kg bw/day.

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

Modified dose descriptor starting point:

NOAEC

Value:

16.63 mg/m³

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 of REACH Regulation (EC) No 1907/2006, Annex VIII, section 8.6.1 (see IUCLID section 7.5.2).

AF for dose response relationship:

1

Justification:

NOAEL (human, oral) value used for calculations

AF for differences in duration of exposure:

1

Justification:

Recommended AF (for chronic exposure) ECHA REACH Guidance document R8, 2012

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable, derived from human data

AF for other interspecies differences:

1

Justification:

Not applicable, derived from human data

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to the discussion

AF for the quality of the whole database:

1

Justification:

Please refer to the discussion

AF for remaining uncertainties:

1

Justification:

Please refer to the discussion

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:

95 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

Modified dose descriptor starting point:

NOAEL

Value:

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

AF for dose response relationship:

1

Justification:

NOAEL (human, oral) value used for calculations

AF for differences in duration of exposure:

1

Justification:

Recommended AF (for chronic exposure) ECHA REACH Guidance document R8, 2012

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable, derived from human data

AF for other interspecies differences:

1

Justification:

Not applicable, derived from human data

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to the discussion

AF for the quality of the whole database:

1

Justification:

Please refer to the discussion

AF for remaining uncertainties:

1

Justification:

Please refer to the discussion

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:

9.5 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

Modified dose descriptor starting point:

NOAEL

Value:

9.5 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:

NOAEL (human, oral) value used for calculations

AF for differences in duration of exposure:

1

Justification:

Recommended AF (for chronic exposure) ECHA REACH Guidance document R8, 2012

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable, derived from human data

AF for other interspecies differences:

1

Justification:

Not applicable, derived from human data

AF for intraspecies differences:

1

Justification:

Not applicable, please refer to the discussion

AF for the quality of the whole database:

1

Justification:

Please refer to the discussion

AF for remaining uncertainties:

1

Justification:

Please refer to the discussion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Value:

28.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose 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:

medium 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.

DNEL long-term inhalation, systemic effects

According to ECHA guidance document CSA: R8, 2012, for dust if the derived DNEL for inhalation is above the general dust limit (10 mg/m³), then the general dust limit should be applied. As the calculated DNEL long-term inhalation for lithium sulfate and lithium sulfate monohydrate was determined to be 16.63 mg/m³ and 19.36 mg/m³, respectively (see below *), the DNEL considered for risk characterisation is the general dust limit of 10 mg/m³.

* An inhalation NOAEC was derived by route-to-route extrapolation (ECHA CSR R8, 2012) from the lithium NOAEL long-term oral (human) value of 1.2 mg Li/kg bw/day, corresponding to 84 mg Li/person/day (60 kg/person x 1.2 mg Li/kg bw/day), as lithium is the toxicological relevant component of lithium sulfate (obtained from human data, long-term (chronic) treatment of bipolar disorder with lithium carbonate, see IUCLID section 7.5). The oral, long-term (human) NOAEL of 1.2 mg Li/kg bw/day was converted to an inhalation NOAEC (human), assuming, 60 kg body weight for general population, 100 % absorption via the lung, 50 % absorption via the oral route and a daily exposure period of 24 hours (corresponding to breathing volume of 20 m³/day). Accordingly, a NOAEC of 2.1 mg Li/m³ equivalent to 16.63 mg Li2SO4 /m³ and 19.36 mg Li2SO4*H2O/m³ was calculated.

NOAEC (general population) inhalation = 84 mg Li/person/day * (1 / 20 m³/person/day(24h)) * (50 % Abs./ 100 % Abs.) = 2.1 mg Li/m³

= 16.63 mg Li2SO4/m³

= 19.36 mg Li2SO4*H2O/m³.

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 DNEL long-term inhalation (general population) is 16.63 mg Li2SO4/m³ and 19.36 mg Li2SO4/m³ (16.63 mg Li2SO4/m³ : 1 (AFs), 19.36 mg Li2SO4*H2O/m³ : 1 (AFs)).

DNEL long-term dermal, systemic

The NOAEL long-term dermal of 95.0 mg Li2SO4/kg bw/day and 110.6 mg Li2SO4*H2O/kg bw/day were calculated from the NOAEL long-term oral of 9.50 mg Li2SO4/kg bw/day and 11.06 mg Li2SO4*H2O/kg bw/day considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2012, 7.12).

NOAEL (Li2SO4) long-term dermal = 9.5 mg/kg bw/day x 100% : 10% = 95 mg Li2SO4/kg bw/day;

NOAEL (Li2SO4*H2O) long-term dermal = 11.06 mg/kg bw/day x 100% : 10% = 110.6 mg Li2SO4*H2O/kg bw/day.

The NOAEL long-term oral and thus the NOAEL long-term dermal are based on lithium toxicity as lithium is the toxicological relevant component of lithium sulfate. 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 DNEL long-term dermal (Li2SO4) = 95.0 mg Li2SO4/kg bw/day : 1 (AFs) = 95.0 mg Li2SO4/kg bw/day and

DNEL long-term dermal (Li2SO4*H2O) = 110.6 mg Li2SO4*H2O/kg bw/day : 1 (AFs) = 110.6 mg Li2SO4*H2O/kg bw/day.

DNEL lomg-term oral, systemic effects

The toxicological relevant component of lithium sulfate is lithium. Thus, the NOAEL long-term oral was calculated to be 9.50 mg Li2SO4/kg bw/day and 11.06 mg Li2SO4*H2O/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). For lithium sulfate and lithium sulfate monohydrate DNEL long-term oral derivation, an AF for exposure duration was not applicable as data available 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 9.50 mg Li2SO4/kg bw/day and 11.06 mg Li2SO4*H2O/kg bw/day

(9.50 mg Li2SO4/kg bw/day : 1 (AFs), 11.06 mg Li2SO4*H2O/kg bw/day : 1 (AFs)).