Lithium hydroxide

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:

14.47 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 section IUCLID 7.5.2).

AF for dose response relationship:

1

Justification:

NOAEL 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, 2010

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable according to ECHA REACH Guidance document R8, 2010

AF for other interspecies differences:

1

Justification:

Not applicable, derived from human data

AF for intraspecies differences:

1

Justification:

Not applicable, see below in the discussion

AF for the quality of the whole database:

1

Justification:

See below in the discussion

AF for remaining uncertainties:

1

Justification:

See below in the discussion

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

30 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

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:

41.35 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:

41.35 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 value used for calculations

AF for differences in duration of exposure:

1

Justification:

Recommended AF (for chronic exposure) ECHA REACH Guidance document R8, 2010

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, see below in discussion

AF for the quality of the whole database:

1

Justification:

See below in discussion

AF for remaining uncertainties:

1

Justification:

See below in discussion

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation was required.

AF for dose response relationship:

1

Justification:

LD0 value was used for calculation.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to human according to ECHA REACH Guidance document R8, 2010

AF for other interspecies differences:

1

Justification:

There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

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 assessemnt factors are required.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

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, 2010, for significantly soluble dust as in the case with lithium hydroxide and lithium hydroxide monohydrate, 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 hydoxide and lithium hydroxide monohydrate was determined to be 14.47 mg/m³ and 25.35 mg/m³, respectively (see below *), the DNEL considered for risk characterisation is the general dust limit – 10 mg/m³.

* An inhalation NOAEC was derived by route to route extrapolation (ECHA CSR R8, 2010) 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 hydroxide (obtained from human data, long-term (chronic) treatment of bipolar disorder with lithium carbonate, see section 7.5 in the IUCLID). 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 14.47 mg LiOH /m³ and 25.35 mg LiOH*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 = 14.47 mg LiOH/m³ = 25.35 mg LiOH*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, humans which are physically fit and being applicable to all sub-populations), thus, relevant to worker and general population. The resulting worker DNEL long-term inhalation = 14.47 mg LiOH/m³/day and 25.35 mg LiOH*H2O/m³/day (14.47 mg/m³/day : 1 (AFs), 25.35 mg/m³/day : 1 (AFs)).

DNEL long-term dermal, systemic

The NOAEL long-term dermal of 41.35 mg LiOH/ kg bw/day and 72.43 mg LiOH*H2O/ kg bw/day were calculated from the NOAEL long-term oral of 4.135 mg LiOH/ kg bw/day and 7.234 mg LiOH*H2O7 kg bw/day considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2008, 7.12)

NOAEL (LiOH) long-term dermal = 4.135 mg/kg bw/day x 100 : 10 = 41.35 mg/kg bw/day; NOAEL (LiOH*H2O) long-term dermal = 7.234 mg/kg bw/day x 100 : 10 = 72.43 mg/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 hydroxide. 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 a 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 and being applicable to all sub-populations), thus, relevant for worker and general population.

The resulting DNEL long-term dermal (LiOH) = 41.35 mg LiOH/kg bw/day : 1 (AFs) = 41.35 mg LiOH/ kg bw/day and DNEL long-term dermal (LiOH*H2O) = 72.43 mg LiOH*H2O/kg bw/day : 1 (AFs) = 72.43 mg LiOH*H2O/ kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.21 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:

6.21 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 value used for calculations

AF for differences in duration of exposure:

1

Justification:

Recommended AF (for chronic exposure) ECHA REACH Guidance document R8, 2010

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, see below in discussion

AF for the quality of the whole database:

1

Justification:

see below in discussion

AF for remaining uncertainties:

1

Justification:

see below in discussion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Value:

18.63 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

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:

41.35 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:

41.35 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 value used for calculations

AF for differences in duration of exposure:

1

Justification:

Recommended AF (for chronic exposure) ECHA REACH Guidance document R8, 2010

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, see below in discussion

AF for the quality of the whole database:

1

Justification:

See below in discussion

AF for remaining uncertainties:

1

Justification:

See below in discussion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Value:

50 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation was required.

AF for dose response relationship:

1

Justification:

LD0 value was used for calculation.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to human according to ECHA REACH Guidance document R8, 2010

AF for other interspecies differences:

1

Justification:

There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

10

Justification:

The default value for the group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of teh 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 assessemnt factors are required.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.13 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:

4.13 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 value used for calculations

AF for differences in duration of exposure:

1

Justification:

Recommended AF (for chronic exposure) ECHA REACH Guidance document R8, 2010

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, see below in the discussion

AF for the quality of the whole database:

1

Justification:

See below in the discussion

AF for remaining uncertainties:

1

Justification:

See below in the discussion

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.4 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

An inhalation NOAEC was derived by route-to-route extrapolation (ECHA CSR R8, 2010) from the lithium NOAEL long-term oral (human) value of 1.2 mg Li/kg bw/day, corresponding to 72 mg Li/person/day (60 kg/person x 1.2 mg Li/kg bw/day), as lithium is the toxicological relevant component of lithium hydroxide (obtained from human data, long-term (chronic) treatment of bipolar disorder with lithium carbonate, see section 7.5 in the IUCLID). 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 (gerenal public), 100 % absorption via the lung, 50 % absorption via the oral route and a daily exposure period of 24 hours during light activity (corresponding to breathing volume of 20 m³/day). Accordingly, a NOAEC of 1.8 mg Li/m³ equivalent to 6.21 mg LiOH /m³ and 10.88 mg LiOH*H2O/m³ was calculated.

NOAEC (general population) inhalation = 72 mg Li/person/ day * (1 / 20 m³/person/day(24h)) * (50 % Abs. / 100 % abs.) = 1.8 mg Li/m³ = 6.21 mg LiOH/m³ = 10.88 mg LiOH*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 and being applicable to all sub-populations), thus, relevant to worker and general population. The resulting worker DNEL long-term inhalation = 6.21 mg LiOH/m³/day and 10.88 mg LiOH*H2O/m³/day (6.21  mg/m³/day : 1 (AFs), 10.88  mg/m³/day : 1 (AFs)).

DNEL long-term dermal, systemic effects

The NOAEL long-term dermal of 41.35 mg LiOH/ kg bw/day and 72.43 mg LiOH*H2O/ kg bw/day were calculated from the NOAEL long-term oral of 4.135 mg LiOH/ kg bw/day and 7.234 mg LiOH*H2O/kg bw/day considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2008, 7.12)

NOAEL (LiOH) long-term dermal = 4.135 mg/kg bw/day x 100 : 10 = 41.35 mg/kg bw/day; NOAEL (LiOH*H2O) long-term dermal = 7.234 mg/kg bw/day x 100 : 10 = 72.43 mg/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 hydroxide. 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 a 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 and being applicable to all sub-populations), thus, relevant for worker and general population.

The resulting DNEL long-term dermal (LiOH) = 41.35 mg LiOH/kg bw/day : 1 (AFs) = 41.35 mg LiOH/ kg bw/day and DNEL long-term dermal (LiOH*H2O) = 41.35 mg LiOH*H2O/kg bw/day : 1 (AFs) = 72.43 mg LiOH*H2O/ kg bw/day.

DNEL long-term oral, systemic effects

The NOAEL long-term oral was calculated to be 4.13 mg LiOH/kg bw/day and 7.24 mg LiOH/kg bw/day, based on lithium NOAEL long-term oral of 1.2 mg Li/kg bw/day (obtained from human data, long-term (chronic) treatment of bipolar disorder with lithium carbonate, see section 7.5 in the IUCLID). For lithium hydroxide and lithium hydroxide 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 acceptable to humans, which are physically fit and being applicable to all sub-populations), thus, relevant to general population and worker. The resulting DNEL general population long-term oral = 4.13 mg LiOH/kg bw/day and 7.24 mg LiOH*H2O/kg bw/day (4.13 mg LiOH/kg bw/day : 1 (AFs), 7.24 mg LiOH*H2O/kg bw/day : 1 (AFs)).