Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Based on the current knowledge the statement has been written.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010

Materials and methods

Objective of study:
absorption
Principles of method if other than guideline:
no guideline as it is an expert statement
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Calcium nitrate
EC Number:
233-332-1
EC Name:
Calcium nitrate
Cas Number:
10124-37-5
Molecular formula:
Ca(NO3)2
IUPAC Name:
calcium dinitrate
Test material form:
solid: crystalline
Details on test material:
Mf: Ca(NO3)2
Mw: 164.088 g/mol (anhydrous)
Radiolabelling:
no

Results and discussion

Main ADME results
Type:
absorption
Results:
50% absorption is taken for oral, dermal and inhalation exposure.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on low MW, high water solubility, assumed low logPow high absorption is expected. However, the ion formation of the substance inmediately when in contact with a fluid decreases the absorption. The guidance has also been taken into consideration. Therefore, 50% absorption is taken for oral, dermal and inhalation exposure.

Any other information on results incl. tables

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration (1). Based on the relatively high water solubility (>10 g/L) nitrate compounds are expected to have the potential to be absorbed by passive diffusion and may pass through aqueous pores or be carried through the epithelial barriers by the bulk passage of water. While calcium nitrate double salt (CN-Nitcal) has a high molecular weight (900) which is not favourable for absorption, the relatively low molecular weight of most nitrate compounds (for calcium nitrate, potassium nitrate, magnesium nitrate and sodium nitrate, all below 200) is favourable for absorption.On the other hand, calcium nitrate, magnesium nitrate, potassium nitrate, sodium nitrate and CN-Nitcal being all water soluble salts, will dissociate into the calcium/magnesium/potassium/sodium cation and the nitrate anion, which will impair the passage of the gastrointestinal wall (1). Although a partition coefficient cannot be determined for these nitrate substances, it is considered to be low, due to the chemical properties, and not favourable for uptake from the gastrointestinal tract. For risk assessment purposes, the oral absorption is set at 50%. The results of the toxicity studies do not provide reason to deviate from this proposed oral absorption.

Once absorbed, widely distribution of all nitrate substances throughout the body, by means its dissociation products, is expected based on its relatively low molecular weight and high water solubility. Based on its hydrophilic character and ion formation, the extracellular concentration is expected to be higher than intracellular concentration. It is expected that the ions will be excreted mainly via the urine (low molecular weight compounds).

The high melting point (above 100˚C) and boiling point and low vapour pressure (both expected to be high based on the lack of melting at temperatures up to 300˚C), indicate that it is not likely that vapours of the nitrate substances will reach the nasopharyngeal region or subsequently the tracheobronchial or pulmonary region. In addition, the particle size of these substances is much higher than 100μm with only a negligible fraction below 100μm, and thus having no or limited potential to be inhaled.Particles between 100 and 10μm will deposit in the nasopharyngeal region and subsequently be coughed or sneezed out of the body or swallowed. However, particles below 10μm might reach the tracheobronchial or pulmonary regions (2), and then absorption through aqueous pores will be likely taking the molecular weight of <200 into account (although less for the high molecular weight compound CN-Nitcal). The high water solubility of all nitrate substances (> 10 g/L) is favourable for dissolution of the substance in the mucus lining of the respiratory tract.The assumed low partition coefficient of the nitrate substances is, however, indicative for low potential of absorption directly across the respiratory tract epithelium. Overall, it is concluded that when calcium nitrate, magnesium nitrate, potassium nitrate, sodium nitrate or CN-Nitcal is inhaled (particles <10μm only), absorption of these substances is to be expected, and for risk assessment purposes the inhalation absorption for these substances is set at 50%.

Calcium nitrate, magnesium nitrate, potassium nitrate, sodium nitrate and CN-Nitcal are being very well water soluble substances and thus have the potential to be absorbed dermally as the surface moisture of the skin will not limit the availablility. The low molecular weights and high water solubility of these substances are favourable for dermal uptake, although the higher molecular weight of CN-Nitcal is less favourable for dermal uptake. Although a partition coefficient cannot be determined for these substances, it is considered to be low. The criteria for reduced dermal absorption (10%) as given in the REACH guidance, Chapter R7c. (2) (MW>500 and log Pow is smaller than -1 or higher than 4) are not met, and therefore 100% dermal absorption should be considered for risk assessment purposes. Since it is assumed that dermal absorption will not exceed oral absorption, the oral absorption of 50% may be considered as a more realistic value for dermal absorption of calcium nitrate, magnesium nitrate, potassium nitrate, sodium nitrate and CN-Nitcal.

Applicant's summary and conclusion