Lithium chloride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.5 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

6

Dose descriptor starting point:

NOAEL

Value:

17 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

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 section IUCLID 7.5.2).  

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:

2

Justification:

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

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation (ECHA REACH Guidance document R8, 2012).

AF for other interspecies differences:

1

Justification:

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

AF for intraspecies differences:

3

Justification:

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Differences in renal clearance or sensitivity to the side effects are well covered by a factor of 3. For more information please refer to "Additional information".

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)

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9.9 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

24

Dose descriptor starting point:

NOAEL

Value:

17 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

238 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Using a conservative approach, a worker DNEL (long-term dermal exposure) is derived. Based on the physico-chemical properties of Li2CO3 dermal absorption is considered to be 10% of oral absorption. 

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:

2

Justification:

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

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA REACH document R.8 2012 the default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

AF for intraspecies differences:

3

Justification:

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Differences in renal clearance or sensitivity to the side effects are well covered by a factor of 3. For more information please refer to "Additional information".

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

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

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

General

DNEL derivation for each of the relevant endpoints was based on the most conservative dose descriptors obtained. Both human and animal data were evaluated and assessment factors were assigned accordingly. The combined data set was used in a WoE to derive reliable and conservative DNELs for the risk assessment.

Guideline and GLP compliant animal studies are available from read-across with lithium carbonate (OECD 416 and OECD 414). No specific effects were noted on functional operation battery, reproductive parameters or on the offspring in these studies. However, systemic effects were observed in both parental generations at 45 mg/kg bw/d.

Lithium chloride and lithium carbonate are also used since decades for the long-term treatment of bipolar disorders. Thus, from the use as a drug, there are human data available that need to be taken into account in deriving respective DNELs.

The DNELs were therefore derived both from reliable human data (long term, oral administration of lithium carbonate) as well as from the animal data retrieved from the OECD 416 study (read-across to lithium carbonate). It should be noted, that the rat seems to be more sensitive than humans based on the available data.

In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Hazard via inhalation route

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 chloride was determined to be 8.5 mg/m³ (human data) and 3.5 mg/m³ (animal data), the DNEL considered for risk characterisation is 3.5 mg/m³.

1. Using the human NOAEL value:

An inhalation NOAEC was derived by route-to-route extrapolation (ECHA CSA R8, 2012) from the lithium NOAEL long-term oral (human) value of 7.32 mg LiCl/kg bw/day. This value is derived from the recommended daily application for a  long-term treatment of bipolar disorder with lithium carbonate (see section 7.5 in the IUCLID) of 450 mg lithium carbonate/person/day divided by a body weight of 70 kg/person. It should be noted that the human NOAEL for possible developmental effects is higher as determined in the study of Patorno et al, 2017 with 600 mg of lithium per person per day (8.6 mg /kg bw/day). Thus a DNEL derived from the drug application in humans can be considered to be protective for possible developmental effects as well. The oral, long-term (human) NOAEL of 7.32 mg LiCl/kg bw/day was converted to an inhalation NOAEC (human), assuming, 70 kg body weight for worker, a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route) and a daily exposure period of 8 hours during light activity (corresponding to breathing volume of 10 m³/day). Accordingly, a NOAEC of 25.62 mg LiCl/m³ was calculated.

NOAEC (worker) inhalation = 7.32 mg/kg bw/ day * 70 kg * (1 / 10m³/person/day(8h)) * (50 % Abs. / 100 % abs.) = 25.62 mg/m³

An additional AF of 3 was applied to cover the risk/benefit approach and the potential for very minor side effects considered to be acceptable for a drug (LOEL versus NOEL). This is considered a conservative approach considering the steep dose-response curve of lithium salts. No AF for exposure duration was 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 not 100% healthy humans and being applicable to all sub-populations), thus,  relevant to worker and general population.

The resulting worker DNEL long-term inhalation = 25.62 mg/m³ : 3 = 8.5 mg/m³.

2. Using the animal NOAEL value:

An inhalation NOAEC was derived by route to route extrapolation (ECHA CSR R8, 2012) from the NOAEL long-term oral (rat) value of 17 mg lithium chloride/kg bw/day obtained from animal data (OECD 416), long-term (subchronic) treatment with lithium carbonate (see section 7.8 in the IUCLID). The oral, long-term NOAEL of 17 mg lithium chloride/kg bw/day was converted to an inhalation NOAEC, assuming, 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).

Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 17 mg/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50/100

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/day

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker=1.4

Corrected NOAEC (inhalation) for workers:

= 17 mg/kg bw/day× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³) × 1.4

= 21 mg/m³

Assessment factors:

Overall AF= 6

Interspecies AF (allometric scaling): According to Table R.8.4 in chapter R.8 of the ECHA Guidance Document no AF is needed when route (oral)-to route (inhalation) is applied.

Intraspecies AF: 3

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Only differences in renal clearance or sensitivity  to the side effects play a role. Due to the huge data base on human pharmaceutical uses, it seems that the sensitivity differences are not particularly big and mainly related to renal function. Boer et al. described 10 to 20% interindividual variation of Li excretion which would be covered with a factor 3 even  in the general population. Findling et al, 2010 and Landersdorfer et al, 2016 did not find higher sensitivity in children treated with Lithium salts. Yamaguchi et al. 2019 confirmed that differences in sensitivity to lithium salts in patients are solely correlated with the lithium serum concentration and the differences in renal clearance as indicated above.

Interspecies AF, remaining differences: 1

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

Exposure duration AF (2-gen study): 2

The repeated dose oral toxicity study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion, long term systemic inhalation DNEL, workers = 21 mg/m³ / 6 = 3.5 mg/m³

The data at hand suggest that the rat is more sensitive to effects than humans and more AF are used for extrapolation. Thus, the DNEL to be used in the risk assessment is based on the lower value derived from the animal (rat) data to be very conservative.

Short term inhalation, systemic

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, "a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute inhalation toxicity. Therefore, a DNEL is not required.

Short term and long term inhalation, local

The test item is classified for eye irritation according Regulation (EC) No 1272/2008 (CLP). This implies that a potential damage to mucosal tissue may occur by inhalative exposure. Based on the observations indicated in an acute inhalation study this assumption could not be concluded or excluded. Additionally, no threshold data could be derived from the respective studies/data. Thus, qualitative approach was applied to hazard and risk assessment with relevant RMM (ECHA CSA R.8, 2012).

Hazard via dermal route

Long term dermal, systemic

1. Using the human NOAEL value:

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. This value is derived from the recommended daily application for a long-term treatment of bipolar disorder with lithium carbonate (see section 7.5 in the IUCLID) of 450 mg lithium carbonate/person/day divided by a body weight of 70 kg/person. It should be noted that the  human NOAEL for possible developmental effects is higher as determined in the study of Patorno et al, 2017 with 600 mg of lithium per person per day (8.6 mg /kg bw/day). Thus a DNEL derived from the drug application in humans can be considered to be protective for possible developmental effects as well. The oral, long-term (human) NOAEL of 7.32 mg LiCl/kg bw/day was converted to a dermal NOAEL (human) 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

An additional AF of 3 was applied to cover the risk/benefit approach and the potential for very minor side effects considered to be acceptable for a drug (LOEL versus NOEL). This is considered a conservative approach considering the steep dose-response curve of lithium salts. No AF for exposure duration was 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 not 100% healthy humans and being applicable to all sub-populations), thus,  relevant to worker and general population. The resulting DNEL long-term dermal = 73.2 mg /kg bw/day : 3 = 24.4 mg /kg bw/day.

2. Using the animal NOAEL value:

In order to derive the worker DNEL (long-term dermal exposure), the NOAEL assessed in the two-generation toxicity study (OECD 416) is identified as the relevant dose descriptor. Assuming that dermal absorption is 10 % of the applied test substance and the oral absorption in rats is 100 % as a worst case, and considering the appropriate modification and assessment factors, the worker DNEL (long-term dermal exposure) is calculated.

Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 17 mg/kg bw/day

Factor for dermal NOAEL= 100 % oral / 10 % dermal= 10

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 5 days/week

NOAEL_corr = 17 mg/kg bw/day * 10 * (7/5) = 238 mg/kg bw/day

Assessment factors:

Overall AF= 24

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 1

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

Intraspecies AF (worker): 3

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Only differences in renal clearance or sensitivity  to the side effects play a role. Due to the huge data base on human pharmaceutical uses, it seems that the sensitivity differences are not particularly big and mainly related to renal function. Boer et al. described 10 to 20% interindividual variation of Li excretion which would be covered with a factor 3 even  in the general population. Findling et al, 2010 and Landersdorfer et al, 2016 did not find higher sensitivity in children treated with Lithium salts. Yamaguchi et al. 2019 confirmed that differences in sensitivity to lithium salts in patients are solely correlated with the lithium serum concentration and the differences in renal clearance as indicated above.

Exposure duration AF: 2

In conclusion, long term systemic dermal DNEL, workers = 238 mg/kg bw/d / 24 = 9.9 mg/kg bw/day

Although the data at hand suggest that the rat is more sensitive to effects than humans and more AF are used for extrapolation, the DNEL to be used in the risk assessment is based on the lower value derived from the animal (rat) data to be very conservative.

Short term dermal, systemic

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

Short term and long term dermal, local

The test item is classified for skin irritation, Cat. 2 (H315) according Regulation (EC) No 1272/2008 (CLP). Therefore, it is allocated to the low hazard band according to ECHA guidance part E (2016).

Hazard to the eyes

The test item is classified for eye irritation (H319) according Regulation (EC) No 1272/2008 (CLP). Therefore, it is allocated to the low hazard band according to ECHA guidance part E (2016).

References

(not included as endpoint study record)

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. November 2012.

- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2014.

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

- ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016.

- Boer, W. H. et al. (1989). Small intra- and large inter-individual variability in lithium clearance in humans. Kidney International, 35, 1183-1188.

- Findling, R. L. et al. (2010). First-Dose Pharmacokinetics of Lithium Carbonate in Children and Adolescents. J Clin Psychopharmacol, 30(4), 404-410. https://doi:10.1097/JCP.0b013e3181e66a62.

- Landersdorfer, C. B. (2017). Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics. Clin. Pharmacokinet, 56, 77-90. https://doi.org/10.1007/s40262-016-0430-3

- Yamaguchi, D. et al. (2019). Population Pharmacokinetics and Exposure–Response of Lithium Carbonate in Patients Based on Tubular Reabsorption Mechanisms. Eur J Drug Metab Pharmacokinet, 44, 329-338. https://doi.org/10.1007/s13318-018-0536-0

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.56 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

5.56 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:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

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

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrap
olation (ECHA REACH Guidance document R8, 2012).

AF for other interspecies differences:

1

Justification:

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

AF for intraspecies differences:

5

Justification:

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Differences in renal clearance or sensitivity to the side effects are well covered by a factor of 5 as aworst case for the general population. For more information please refer to "Additional information".

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)

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.75 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

150 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:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

Extrapolation from subchronic to chronic exposure (ECHA REACH Guidance document R8, 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA REACH document R.8 2012 the default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

AF for intraspecies differences:

5

Justification:

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Differences in renal clearance or sensitivity to the side effects are well covered by a factor of 5 as aworst case for the general population. For more information please refer to "Additional information".

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

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:

0.38 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

15 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:

2

Justification:

Extrapolation from subchronic to chronic exposure (ECHA REACH Guidance document R8, 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA REACH document R.8 2012 the default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

AF for intraspecies differences:

5

Justification:

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Differences in renal clearance or sensitivity to the side effects are well covered by a factor of 5 as aworst case for the general population. For more information please refer to "Additional information".

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:

1.14 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

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:

low hazard (no threshold derived)

Additional information - General Population

General

DNEL derivation for each of the relevant endpoints was based on the most conservative dose descriptors obtained. Both human and animal data were evaluated and assessment factors were assigned accordingly. The combined data set was used in a WoE to derive reliable and conservative DNELs for the risk assessment.

Guideline and GLP compliant animal studies are available for the substance (OECD 416 and OECD 414). No specific effects were noted on functional operation battery, reproductive parameters or on the offspring in these studies. However, systemic effects were observed in both parental generations at 45 mg/kg bw/d. In addition, a very steep dose-response curve was seen in animal studies.

Lithium carbonate is also used since decades for the long-term treatment of bipolar disorders. Thus, from the use as a drug, there are human data that need to be taken into account in deriving respective DNELs.

The DNELs were therefore derived both from reliable human data (long term, oral administration as drug) as well as from the animal data retrieved from the OECD 416 study. It should be noted, that the rat seems to be more sensitive to lithium carbonate toxicity than humans based on the available data.

In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Hazard via inhalation route

Long term inhalation, systemic

As the calculated DNEL long-term inhalation for lithium carbonate was determined to be 3.21 mg/m³ (human data) and 0.56 mg/m³ (animal data), the DNEL considered for risk characterisation is 0.56 mg/m³.

1. Using the human NOAEL value:

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. This value is derived from the recommended daily application for a long-term treatment of bipolar disorder with lithium carbonate (see section 7.5 in the IUCLID) of 450 mg lithium carbonate/person/day divided by a body weight of 70 kg/person. It should be noted that the human NOAEL for possible developmental effects is higher as determined in the study of Patorno et al, 2017 with 600 mg of lithium per person per day (8.6 mg /kg bw/day). Thus, a DNEL derived from the drug application in humans can be considered to be protective for possible developmental effects as well. 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), a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting 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 = 6.43 mg/kg bw/day * 60 kg * (1 / 20 m³/person/day(24h)) * (50 % Abs. / 100 % abs.) = 9.64 mg/m³

An additional AF of 3 was applied to cover the risk/benefit approach and the potential for very minor side effects considered to be acceptable for a drug (LOEL versus NOEL). This is considered a conservative approach considering the steep dose-response curve of lithium carbonate. No AF for exposure duration was 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 not 100% healthy humans 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/m³ : 3 = 3.21 mg/m³.

2. Using the animal NOAEL value:

An inhalation NOAEC was derived by route to route extrapolation (ECHA CSR R8, 2012) from the NOAEL long-term oral (rat) value of 15 mg/kg bw/day obtained from animal data, long-term (subchronic) treatment with lithium carbonate (see section 7.8.1 in the IUCLID). The oral, long-term NOAEL of 15 mg/kg bw/day was converted to an inhalation NOAEC, assuming, 100 % absorption via the lung, 50 % absorption via the oral route and a daily exposure period of 24 hours, resulting in a DNEL of 0.56 mg/m³.

Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 15 mg/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50/100

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.35 m³/kg bw

Differences experimental/human exposure conditions: 7d/24h rat vs.7d/24h (general population)

NOAEC_corr = 15 mg/kg bw/day× 0.5 × (1 / 1.35 m³/kg bw/24h) x 1 = 5.56 mg/m³

Assessment factors:

Overall AF= 10

Interspecies (allometric scaling): According to Table R.8.4 in chapter R.8 of the ECHA Guidance Document no AF is needed when route (oral)-to route (inhalation) is applied.

Intraspecies AF: 5

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Only differences in renal clearance or sensitivity  to the side effects play a role. Due to the huge data base on human pharmaceutical uses, it seems that the sensitivity differences are not particularly big and mainly related to renal function. Boer et al. described 10 to 20% inter-individual variation of Li excretion which would be covered with a factor 3 even  in the general population. Findling et al, 2010 and Landersdorfer et al, 2017 did not find higher sensitivity in children treated with Lithium salts. Yamaguchi et al. 2019 confirmed that differences in sensitivity to lithium salts in patients are solely correlated with the lithium serum concentration and the differences in renal clearance as indicated above. An AF of 5 was used for the general population as worst case.

Interspecies AF, remaining differences: 1

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

Exposure duration AF (subchronic to chronic): 2

In conclusion, long term systemic inhalation DNEL, general population = 5.56 mg/m³ / 3 = 0.56 mg/m³

Although the data at hand suggest that the rat is more sensitive to effects than humans and more AF are used for extrapolation, the DNEL to be used in the risk assessment is based on the lower value derived from the animal (rat) data to be very conservative.

Short term inhalation, systemic

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, "a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute inhalation toxicity. Therefore, a DNEL is not required.

Short term and long term inhalation, local

The test item is classified for eye irritation according Regulation (EC) No 1272/2008 (CLP). This implies that a potential damage to mucosal tissue may occur by inhalation exposure. Based on the observations indicated in an acute inhalation study this assumption could not be concluded or excluded. Additionally, no threshold data could be derived from the respective studies/data. Thus, a qualitative approach was applied to hazard and risk assessment with relevant RMM (ECHA CSA R.8, 2012 and part E, 2016).

Hazard via dermal route

Long term dermal, systemic

1. Using the human NOAEL value:

The NOAEL long-term dermal of 64.3 mg lithium carbonate/kg bw/day was calculated from the NOAEL long-term oral (human) value of 6.43 mg lithium carbonate/kg bw/day. This value is derived from the recommended daily application for a long-term treatment of bipolar disorder with lithium carbonate (see section 7.5 in the IUCLID) of 450 mg lithium carbonate/person/day divided by a body weight of 70 kg/person. It should be noted that the human NOAEL for possible developmental effects is higher as determined in the study of Patorno et al, 2017 with 600 mg of lithium per person per day (8.6 mg /kg bw/day). Thus, a DNEL derived from the drug application in humans can be considered to be protective for possible developmental effects as well. The oral, long-term (human) NOAEL of 6.43 mg lithium carbonate/kg bw/day was converted to a dermal NOAEL (human), assuming 60 kg body weight (general population) and considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2012, 7.12) -> NOAEL long-term dermal = 6.43 mg/kg bw/day * 60 kg * 100 : 10 = 38.6 mg/kg bw/day.

An additional AF of 3 was applied to cover the risk/benefit approach and the potential for very minor side effects considered to be acceptable for a drug (LOEL versus NOEL). This is considered a conservative approach considering the steep dose-response curve of lithium carbonate. No AF for exposure duration was 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 not 100% healthy humans and being applicable to all sub-populations), thus, relevant to worker and general population. The resulting general population DNEL long-term dermal = 38.6 mg/kg bw/day : 3  = 12.9 mg/kg bw/day.

2. Using the animal NOAEL value:

In order to derive the DNEL (long-term dermal exposure) for the general population, the NOAEL assessed in the two generation reproductive toxicity study (OECD 416) is identified as the relevant dose descriptor. Assuming that dermal absorption is 10 % of the applied test substance and the oral absorption in rats is 100 % as a worst case, and considering the appropriate modification and assessment factors, the general DNEL (long-term dermal exposure) is calculated as 3.75 mg/kg bw/day.

Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 15 mg/kg bw/day

Factor for dermal NOAEL= 100 % oral / 10 % dermal= 10

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 7 days/week

NOAEL_corr =  15 mg/kg bw/day * 10 * (7/7) =150 mg/kg bw/day dermal NOAEL

Assessment factors:

Overall AF: 40

Interspecies AF, allometric scaling (rat to human): 4

Intraspecies AF (general population): 5

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Only differences in renal clearance or sensitivity to the side effects play a role. Due to the huge data base on human pharmaceutical uses, it seems that the sensitivity differences are not particularly big and mainly related to renal function. Boer et al. described 10 to 20% inter-individual variation of Li excretion which would be covered with a factor 3 even in the general population. Findling et al, 2010 and Landersdorfer et al, 2016 did not find higher sensitivity in children treated with Lithium salts. Yamaguchi et al. 2019 confirmed that differences in sensitivity to lithium salts in patients are solely correlated with the lithium serum concentration and the differences in renal clearance as indicated above. An AF of 5 was used for the general population as worst case.

Interspecies AF, remaining differences: 1

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

Exposure duration AF: 2 

In conclusion, long term systemic dermal DNEL, general population  = 150 mg/kg bw/day / 40 = 3.75 mg/kg bw/day

Although the data at hand suggest that the rat is more sensitive to effects than humans and more AF are used for extrapolation, the DNEL to be used in the risk assessment is based on the lower value derived from the animal (rat) data to be very conservative.

Short term dermal, systemic

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified”. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

Short term and long term dermal, local

The test material is not classified and labelled for skin sensitization or skin irritation, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

Hazard via oral route

Long term oral, systemic

1. Using the human NOAEL value:

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). This value is derived from the recommended daily application for a long-term treatment of bipolar disorder (see section 7.5 in the IUCLID) of 450 mg lithium carbonate/person/day divided by a body weight of 70 kg/person. It should be noted that the human NOAEL for possible developmental effects is higher as determined in the study of Patorno et al, 2017 with 600 mg of  lithium per person per day (8.6 mg /kg bw/day). Thus, a DNEL derived from the drug application in humans can be considered to be protective for possible developmental effects as well.

An additional AF of 3 was applied to cover the risk/benefit approach and the potential for very minor side effects considered to be acceptable for a drug (LOEL versus NOEL). This is considered a conservative approach considering the steep dose-response curve of lithium carbonate. No AF for exposure duration was 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 not 100% healthy humans and being applicable to all sub-populations), thus,  relevant to worker and general population. The resulting DNEL general population long term oral = 6.43 mg/kg bw/day : 3 = 2.14 mg/kg bw/day.

2. Using the animal NOAEL value:

In order to derive the worker DNEL (long-term oral exposure), the NOAEL assessed in the two generation reproductive toxicity study (OECD 416) is identified as the relevant dose descriptor. A NOAEL of 15 mg/kg bw/d was used. Considering the appropriate modification and assessment factors, the general DNEL (long-term oral exposure) is calculated as 0.38 mg/kg bw/day.

Overall AF= 40

Interspecies AF, allometric scaling (rat to human): 4

Intraspecies AF (general population): 5

As the lithium cation is not metabolized by physiological enzymes the difference in metabolism contributing to a large portion of the intraspecies assessment factor does not need to be considered in this case. Only differences in renal clearance or sensitivity to the side effects play a role. Due to the huge data base on human pharmaceutical uses, it seems that the sensitivity differences are not particularly big and mainly related to renal function. Boer et al. described 10 to 20% inter-individual variation of Li excretion which would be covered with a factor 3 even in the general population. Findling et al, 2010 and Landersdorfer et al, 2016 did not find higher sensitivity in children treated with Lithium salts. Yamaguchi et al. 2019 confirmed that differences in sensitivity to lithium salts in patients are solely correlated with the lithium serum concentration and the differences in renal clearance as indicated above. An AF of 5 was used for the general population as worst case.

Interspecies AF, remaining differences: 1

There is no metabolism of the lithium ion that could lead to differences in sensitivity between species due to other metabolic pathways or isoenzymes being active. Therefore the interspecies AF remaining differences does not apply.

Exposure duration AF (subchronic to chronic): 2

In conclusion, long term systemic oral DNEL, general population= 15 mg/kg bw/day / 40 = 0.38 mg/kg bw/day.

Although the data at hand suggest that the rat is more sensitive to effects than humans and more AF are used for extrapolation, the DNEL to be used in the risk assessment is based on the lower value derived from the animal (rat) data to be very conservative.

Short term oral, systemic

Lithium carbonate is classified as harmful, if swallowed (H302) according to Regulation (EC) 1272/2008. As no LD0 value could be obtained in the WoEs available for lithium carbonate, the DNEL short term oral for acute oral exposure was based on the DNEL long term oral of 0.38 mg/kg bw/day derived from animal data. The DNEL short term oral was calculated 3-fold the corresponding DNEL long- term oral (ECHA CSR R.8, 2012). As the DNEL acute oral is based on DNEL long term oral, AFs were already considered and therefore no further AFs were applied.

In conclusion, DNEL short term oral = 3 x 0.38 mg/kg bw/day = 1.14 mg/kg bw.

This is considered a very conservative approach as even for long-term exposure in humans a DNEL of 2.14 mg/kg bw/day was deduced.  

References

(not included as endpoint study record)

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. November 2012.

- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2014.

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

- ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016.

- Boer, W. H. et al. (1989). Small intra- and large inter-individual variability in lithium clearance in humans. Kidney International, 35, 1183-1188.

- Findling, R. L. et al. (2010). First-Dose Pharmacokinetics of Lithium Carbonate in Children and Adolescents. J Clin Psychopharmacol, 30(4), 404-410. https://doi:10.1097/JCP.0b013e3181e66a62.

- Landersdorfer, C. B. (2017). Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics. Clin. Pharmacokinet, 56, 77-90. https://doi.org/10.1007/s40262-016-0430-3

- Yamaguchi, D. et al. (2019). Population Pharmacokinetics and Exposure–Response of Lithium Carbonate in Patients Based on Tubular Reabsorption Mechanisms. Eur J Drug Metab Pharmacokinet, 44, 329-338. https://doi.org/10.1007/s13318-018-0536-0