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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:
22.5
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, 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, 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:
64.3 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:
6.43 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, 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:
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, 2012
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 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:
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

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, 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 carbonate was determined to be 22.5 mg/m³ (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, 2012) from the lithium carbonate NOAEL long-term oral (human) value of 6.43 mg lithium carbonate/kg bw/day, corresponding to 450 mg lithium carbonate/person/day (70 kg/person x 6.43 mg lithium carbonate/kg bw/day), 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 6.43 mg lithium carbonate/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 22.5 mg lithium carbonate/m³ was calculated.

NOAEC (worker) inhalation = 450 mg lithium carbonate/person/ day * (1 / 10m³/person/day(8h)) * (50 % Abs. / 100 % abs.) = 22.5 mg lithium carbonate/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 = 22.5 mg lithium carbonate/m³ (22.5 mg/m³ : 1 (AFs)).

DNEL long-term dermal, systemic

The NOAEL long-term dermal of 64.3 mg lithium carbonate/kg bw/day was calculated from the NOAEL long-term oral of 6.43 mg lithium carbonate/ kg bw/day considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2012, 7.12) -> NOAEL long-term dermal = 6.43 mg Li2CO3/kg bw/day x 100 : 10 = 64.3 mg Li2CO3/kg bw/day

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 dermal = 64.3 mg lithium carbonate/kg bw/day (64.3 mg/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:
9.64 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:
9.64 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:
DNEL (Derived No Effect Level)
Value:
28.92 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
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:
64.3 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:
64.3 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, 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:
DNEL (Derived No Effect Level)
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 scalling rat to human according to ECHA REACH document R.8 2012
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 the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conseravtive. No further assessment factors are required.

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:
6.43 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:
6.43 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, 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 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:
19.23 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
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, 2012) from the lithium carbonate NOAEL long-term oral (human) value of 6.43 mg lithium carbonate/kg bw/day, corresponding to 385.8 mg lithium carbonate/person/day (60 kg/person x 6.43 mg lithium carbonate/kg bw/day), 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 6.43 mg lithium carbonate/kg bw/day was converted to an inhalation NOAEC (human), assuming, 60 kg body weight (general population), 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 9.64 mg lithium carbonate/m³ was calculated.

NOAEC (general population) inhalation = 385.8 mg lithium carbonate/person/ day * (1 / 20 m³/person/day(24h)) * (50 % Abs. / 100 % abs.) = 9.64 mg lithium carbonate/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 general population DNEL long-term inhalation = 9.64 mg lithium carbonate/m³ (9.64 mg/m³ : 1 (AFs)).The resulting general population DNEL long-term inhalation of 9.64 mg lithium carbonate/m³ is equivalent to 1.8 mg lithium/m3.

DNEL long-term dermal, systemic

The NOAEL long-term dermal of 64.3 mg lithium carbonate/kg bw/day was calculated from the NOAEL long-term oral of 6.43 mg lithium carbonate/ kg bw/day considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2012, 7.12) -> NOAEL long-term dermal = 6.43 mg Li2CO3/kg bw/day x 100 : 10 = 64.3 mg Li2CO3/kg bw/day

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 general population DNEL long-term inhalation = 64.3 mg lithium carbonate//kg bw/day (64.3 kg bw/day: 1 (AFs)).

DNEL long-term oral, systemic effects

The NOAEL long-term oral was determined to be 6.43 mg lithium carbonate/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 carbonate 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 = 6.43 mg lithium carbonate/kg bw/day (6.43 mg lithium carbonate/kg bw/day : 1 (AFs)).

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