dilithium trimanganese nickel octoxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 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:

NOAEC

Value:

4.2 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 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 "Additional information - Worker"

AF for the quality of the whole database:

1

Justification:

Please refer to "Additional information - Worker"

AF for remaining uncertainties:

1

Justification:

Please refer to "Additional information - Worker"

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:

12 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:

12 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, 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, 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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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. DNELs were recalculated from LiCl to Li taking the molecular weight into account.

DNEL long-term inhalation, systemic

The calculated DNEL long-term inhalation for lithium chloride was determined to be 25.62 mg/m³ (see below *),

* An inhalation NOAEC was derived by route-to-route extrapolation (ECHA CSA R8, 2012) from the lithium NOAEL long-term, human, oral 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 chloride (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 25.62 mg LiCl/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 = 25.62 mg LiCl/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 applicable to all sub-populations), thus, relevant to worker and general population). The resulting calculated worker DNEL long-term inhalation is 25.62 mg LiCl/m³/day (25.62 mg/m³ : 1 (AFs)).

DNEL long-term dermal, systemic

The NOAEL long-term dermal of 73.2 mg LiCl/kg bw/day was calculated from the NOAEL long-term oral of 7.32 mg LiCl/kg bw/day considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2012, 7.12).

NOAEL (LiCl) long-term dermal = 7.32 mg/kg bw/day x 100 : 10 = 73.2 mg LiCl/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 chloride. 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 and applicable to all sub-populations), therefore relevant for worker and general population. The resulting DNEL long-term dermal is 73.2 mg LiCl/kg bw/day (73.2 mg LiCl/kg bw/day : 1 (AFs)).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.8 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:

NOAEC

Value:

1.8 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, 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, 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

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:

12 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:

12 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, 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, 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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

1.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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.

DNELs were recalculated from LiCl to Li taking the molecular weight into account.

DNEL long-term oral, systemic

The toxicological relevant component of lithium chloride is lithium. Thus, the NOAEL long-term oral of lithium chloride was calculated to be 7.32 mg LiCl/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 chloride 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 applicable to all sub-populations), thus, relevant to general population and worker. The resulting DNEL general population long-term oral is 7.32 mg LiCl/kg bw/day (7.32 mg LiCl/kg bw/day : 1 (AFs)).

DNEL long-term inhalation, systemic

The calculated DNEL long-term inhalation for lithium chloride was determined to be 25.62 mg/m³ (see below *), 

* An inhalation NOAEC was derived by route-to-route extrapolation (ECHA CSA R8, 2012) 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 chloride (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 1.8 mg Li/m³ equivalent to 10.98 mg LiCl/m³ was calculated.

NOAEC (general population) inhalation = 72 mg Li/person/ day * (1 / 20m³/person/day(24h)) * (50 % Abs. / 100 % abs.) = 1.8 mg Li/m³ = 10.98 mg LiCl/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 applicable to all sub-populations), thus, relevant to worker and general population. The resulting long-term inhalation DNEL for general population is 10.98 mg LiCl/m³ (10.98 mg/m³ : 1 (AFs)

DNEL long-term dermal, systemic

The NOAEL long-term dermal of 73.2 mg LiCl/kg bw/day was calculated from the NOAEL long-term oral of 7.32 mg LiCl/kg bw/day considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2012, 7.12).

NOAEL (LiCl) long-term dermal = 7.32 mg/kg bw/day x 100 : 10 = 73.2 mg LiCl/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 chloride. 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 and applicable to all sub-populations), therefore relevant for worker and general population. The resulting DNEL long-term dermal is 73.2 mg LiCl/kg bw/day (73.2 mg LiCl/kg bw/day : 1 (AFs)).