Trilithium orthophosphate

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement

Data source

Reference

Reference 1

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2017

Report date:

2017

Reference 2

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2002

Report date:

2002

Reference 3

Reference Type:

review article or handbook

Title:

Manual of clinical psychopharmacology

Author:

Schatzberg, A.F.; Cole, O.J., DeBattista, C.

Year:

2007

Bibliographic source:

American Psychiatric Publishing. ISBN 158562317

Reference 4

Reference Type:

review article or handbook

Title:

Toxicology: the basic science of poisons

Author:

Casarett, L.; Klassen, C.D; Curtis, D.

Year:

2007

Bibliographic source:

ISBN-10: 0-07-147051-4

Reference 5

Reference Type:

review article or handbook

Title:

Physiological Parameters on Laboratory animals and humans

Author:

Davis, B; Morris, T.

Year:

1993

Bibliographic source:

Pharm. res. 10: 1093

Reference 6

Reference Type:

publication

Title:

Endorsement and/or Revision of Maximum Levels for Food Additives in Codex Standards

Author:

Joint FAO/WHO Expert Committee on Food Additives

Year:

2001

Bibliographic source:

Codex Committee on Food Additives and Contaminants, 33. Session, The Hague, The Netherlands, 12-16 March 2001

Reference 7

Reference Type:

publication

Title:

On the phosphate problem

Author:

El-Shaarawy M.I. & Reith J.F.

Year:

1976

Bibliographic source:

Pahlavi Med 7(2):195-213.

Report date:

1976

Reference 8

Reference Type:

secondary source

Title:

The Shocking History of Phosphorus

Author:

Emsley, J.

Year:

2000

Bibliographic source:

Macmillan Publishers Ltd. ISBN 0 333 76638 5. Sited in: Duley, B. (2001): Recycling Phosphorus by Recovery From Sewage, Rhodia Consumer Specialties UK Ltd. (for Centre Europeen d’Etudes des Polyphosphates).

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement on chronic exposure.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Trilithium orthophosphate

EC Number:

233-823-0

EC Name:

Trilithium orthophosphate

Cas Number:

10377-52-3

Molecular formula:

Li3O4P

IUPAC Name:

trilithium orthophosphate

Test material form:

solid

Results and discussion

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

6.67 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

Li3PO4

Sex:

male/female

Basis for effect level:

other: The NOAEL value was based on the NOAEL value of lithium (human data, 1.2 mg/kg bw/day) and calculated for lithium phosphate based on the molecular weight.

2

Key result

Dose descriptor:

NOAEL

Effect level:

85.35 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

Li3PO4

Sex:

male/female

Basis for effect level:

other: The NOAEL value was based on the ADI value of phosphate (human data, 70 mg/kg bw/day) and calculated for lithium phosphate based on the molecular weight.

3

Dose descriptor:

NOAEL

Effect level:

1.2 mg/kg bw/day (nominal)

Based on:

other: NOAEL Lithium

Sex:

male/female

Basis for effect level:

other: NOAEL refers to lithium in human

4

Dose descriptor:

NOAEL

Effect level:

70 mg/kg bw/day (nominal)

Based on:

other: NOAEL/ADI phosphate

Sex:

male/female

Basis for effect level:

other: NOAEL refers to ADI of phosphate in human

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

Based on human data obtained from routine long-term treatment of bipolar disorder with lithium (administered as lithium carbonate), a NOAEL for long-term oral toxicity of 1.2 mg lithium/kg bw/day was calculated. Based on these data, a NOAEL value of 6.67 mg/kg bw/day was calculated for lithium phosphate. Based on the ADI value for phosphate of 70 mg/kg bw/day a NOAEL value of 85.35 mg/kg bw/day for lithium phosphate was calculated.

Executive summary:

No NOAEL/ DNEL/ ADI value is available for lithium phosphate. Nevertheless, NOAEL/ DNEL/ ADI values from human data are available for lithium and for phosphate (see below). Thereof, a NOAEL value based on human data could be derived and calculated for lithium phosphate as detailed below.

Deduced NOAEL/ DNEL value for lithium

In humans, lithium has been used for decades in psychiatric therapy for the treatment of bipolar disorder. In case of long-term treatment, the recommended dose is 450 to 900 mg/day lithium carbonate, equivalent to 84 to 169 mg lithium / day, and corresponding to a desired sustained therapeutic serum concentration of 0.5 to 1.0 mmol lithium/L. Based on experience with long-term application e.g. lithium carbonate for therapy in humans, there is no evidence that lithium is of concern with respect to repeated oral toxicity at medical doses as the ones indicated above.

The effect level (NOAEL) determined for lithium for repeated dose toxicity by the oral route is based on human data and can be calculated in two ways that complete one another:

One option is based on the therapeutic serum concentrations of 0.5 to 1.0 mmol lithium/L and the extracellular fluid (ECF) volume. Lithium has a large volume of distribution of 0.6-0.9 L/kg (42 L for a 70 kg adult, wich is the total body water). It is distributed throughout the body water both extra and intracellularly. Lithium shifts into the intracellular compartments of cells because of its large volume of distribution. Although in long-term use, the intracellular concentration increases, the intracellular concentration is not reflected by the plasma level which measures only the extracellular fluid concentration. Therefore, a desired concentration of 1 mmol/L of lithium is expected to be sustained and reflected in the extracellular fluid (ECF) only and not in the intracellular fluid. Thus, the volume considered is of the ECF only which comprises of plasma, interstitial fluid (spaces between cells) and transcellular fluid (lymph, cerebrospinal fluid, synovial fluid, serous fluid, gastrointestinal secretions) and is typically 15 L (reported in different references to be between 14 – 19 L (for 70 kg adult)). Based on this data the derived NOAEL (considering a lithium concentration of 1 mmol/L and an ECF volume of 15 L) is 1.5 mg/kg bw/day. This NOAEL value can be considered as a conservative value as it is based on an bioavailable dose in humans after absorption and on a smaller volume than its actual distribution volume.

Another way to calculate NOAEL oral for lithium is based as well on data taken from the routine long-term treatment of bipolar disorder. Instead of calculating the NOAEL from the therapeutic serum concentration of lithium, the lithium NOAEL oral can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: 84 to 169 mg lithium / day (corresponding to the desired sustained concentrations of 0.5 -1 mmole lithium/L in blood/serum). When dividing the oral doses (84 to 169 mg lithium / day) to 70 kg, the following values are obtained respectively: 1.2 to 2.4 mg/kg bw/day or when dividing to 60 kg the following values are obtained respectively: 1.4 to 2.8 mg/kg bw/day, representing the optional NOAEL values for lithium for the oral route.

In both ways of calculation, the values obtained are in same order of magnitude and similar to one another. As a worst–case value, a NOAEL repeated dose toxicity oral of 1.2 mg lithium/kg bw was chosen. Further, this value could be used as a starting value for route-to-route extrapolation in calculation of the repeated dose toxicity for the dermal and inhalation routes.

Deduced NOAEL/ DNEL value for phosphate

According to the evaluation of JECFA, 2001 (Joint FAO/WHO Expert Committee on Food Additives), an ADI value (comparable to DNEL) of 70 mg phosphate/kg bw/day was determined.

Derived NOAEL value for lithium phosphate

As detailed above, for calculation of the NOAEL long-term oral of lithium phosphate the following (human) data was available: The NOAEL/DNEL of lithium (1.2 mg lithium/kg bw/day) and the ADI value (comparable to DNEL) of phosphate (70 mg phosphate/kg bw/day). Additionally, the molecular weights of lithium and phosphate were considered.

The calculated NOAEL oral of lithium phosphate (6.67 mg lithium phosphate/kg bw/day) based on the NOAEL of lithium is smaller than the calculated NOAEL of lithium phosphate (85.35 mg lithium phosphate/kg bw/day) based on the ADI of phosphate. Thus, the determined NOAEL oral of lithium phosphate is 6.67 mg lithium phosphate/kg bw/day based on the NOAEL value of lithium being the toxicological limiting value for lithium phosphate.