magnesium bis(dipropan-2-ylazanide)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert Statement

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

other: Expert Statement

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Principles of method if other than guideline:

Expert statement

Test material

Reference

Name:

Unnamed

Type:

Constituent

Type:

Constituent

Administration / exposure

Duration and frequency of treatment / exposure:

Expert statement. No animal study.

Doses / concentrations

Remarks:

Doses / Concentrations:
Expert statement. No animal study.

No. of animals per sex per dose / concentration:

Expert statement. No animal study.

Results and discussion

Preliminary studies:

NA

Toxicokinetic / pharmacokinetic studies

Details on absorption:

MDA is determined by the compounds hydrolysis products Diisopropylamide (DPA) and magnesium hydroxide and magnesium oxide, respectively.

Diisopropylamide (DPA) / adsorption:
DPA was shown to be corrosive in eye irritation and skin irritation studies.
DPA is a liquid with a molecular weight of 101.19 g/mol. Its chemical structure reveals high polarity. Correspondingly its water solubility is relatively high (110 g/L). Its partition coefficient was determined to be logPow = 1.40 and its vapour pressure 79.4 mm Hg.
DPA is rather unlikely to penetrate skin to any significant extent, as although the molecule is rather small and its logPow is > 1, (but also < 2 and thus not optimal for dermal absorption), it is highly polar and highly hydrophilic. Further, with a vapour pressure of 79.4 mm Hg, DPA will evaporate to some extent.

Magnesium oxide (MgO):
MgO is a crystalline mineral of low molecular weight (MW = 40.30 g/mol). Its water solubility is very low (< 1 mg/L). Intake is most likely to occur orally. Naturally, magnesium compounds are taken up in food and drinking water. MgO does not absorb across the skin, however local irritation and corrosion may be caused due to the compounds alkalinity.
Following oral ingestion of magnesium compounds, such as MgO or Mg(OH)2, the sub-stances generally dissociate in the stomach (acid conditions). The available Mg2+ ion is then absorbed along the entire intestinal tract, with the distal jejunum and ileum as sites of maximal magnesium absorption. The net absorption of magnesium is approximately 50 %, depending on dietary constituents.

Details on distribution in tissues:

Diisopropylamide (DPA) / distribution:
If absorbed by skin, systemic DPA toxicity is low, as shown in the acute dermal toxicity study, where no effects were observed. However, local application DPA can cause corrosion to skin and eyes, as the substance is rather alkaline.
Administered orally, DPA is likely to dissolve in the stomach, due to its high water solubility, and may be absorbed via the gastro-intestinal tract. In any case, toxicity to orally administered DPA is low, as shown in acute and subacute toxicity tests.

Magnesium oxide (MgO):
Determined by atomic spectroscopy the total body burden in an average adult is 25 g. Ra-dioactive studies revealed that magnesium is incorporated in all organs; approximately 60 % of that amount is present in bone, 20 % is localised in muscle and the remaining 20 % is present in soft tissue and liver.

Details on excretion:

Diisopropylamide (DPA) / excretion:
See details on metabolites.

Magnesium oxide (MgO):
See details on metabolites.

Metabolite characterisation studies

Details on metabolites:

Diisopropylamide (DPA) / metabolism:
Absorbed by the body, following ingestion or passage through the skin, DPA is likely to be metabolised and the parent compound and degradation products distributed via systemic circulation. During metabolism the hydrophilic DPA may be rendered even more polar. For example, the flavin monooxygenase system could produce the hydroxylamine through N-hydroxylation, catalysed by the flavin monooxygenase system. Several phase I metabolic reactions, including several reduction and hydrolysis reactions, catalysed by cytochrome P-450-dependent monooxygenase enzymes may also occur, including metabolic conversion of the amide group by e.g. N-dealkylation and/or N-hydroxylation. Parent compound and me-tabolites formed in phase I metabolic reactions may be rendered more polar by phase II me-tabolism in subsequent steps. Finally, remaining amounts of the parent compound and formed metabolites are expected to be excreted in urine or bile.
It is unlikely that DPA is metabolised to more reactive (toxic) products. This assumption is supported by results obtained in oral and dermal toxicity studies and two in vitro tests. In both the in vivo studies toxicity was low. In an Ames test and a chromosome aberration assay no significant increase in toxicity was noted in the presence of a rodent microsomal S9-fraction, when compared to incubation without S9-fraction. Together, this data indicates that formation of reactive metabolites is rather unlikely.
Local tissue damage is the main toxicity caused by DPA, due to its irritative nature. Based on the compound’s structure and associated physical-chemical characteristics, bioaccumulation is not likely to occur. Becoming bioavailable, the substance or its metabolites are expected to be well distributed throughout the body fluids and rapidly excreted via urine (non-conjugated forms) or via faces (high molecular weight conjugated forms). Formation of toxic metabolites is unlikely.

Magnesium oxide (MgO):
It has been estimated that 99 % of the total body magnesium is present intracellularly. Of the extracellular fluid magnesium, 75 to 80 % is unfilterable and 20 % is protein bound.
Magnesium is an important element in vitamin D metabolism and/or action. The secretion of parathyroid hormone is stimulated by low concentrations of magnesium. Further, magnesium may cause hypocalcemia. A wide variety of hormones have been implicated in magnesium homeostasis by affecting urinary magnesium excretion, including calcitonin, thyroxine, gluco-corticoids, glucagon and angiotensins.
The kidney is the principal organ involved in magnesium homeostasis. Approximately 80 % of plasma magnesium is unbound and available for glomular filtration by the Kidney. Under normal conditions, 95 % of the filtered load of magnesium is reabsorbed by the kidney and 5 % is excreted in urine. Considerable reabsorption of filtered magnesium is known to occur in the proximal tubules of the kidney.

Applicant's summary and conclusion

Executive summary:

The hydrolysis of MDA in contact with water is spontaneous and takes place instantaneously. In the course of the authorisation according to 67/548/EEC and 92/32/EEC (ID 06-04-2090-00) it was agreed with the German competent authority (BAuA) that no toxicological testing of MDA was carried out. Thus, the toxicokinetic profile of MDA is determined by the compounds hydrolysis products Diisopropylamide (DPA) and magnesium hydroxide and magnesium oxide, respectively. Both, DPA and magnesium are of relatively low acute toxicity. Local irritation may occur, due to the alkaline properties inherent to both compounds. Systemic toxicity is most likely due to secondary effects. Subacute oral administration revealed NOAEL values of 15 mg/kg bw/day and > 1000 mg/kg bw/day for DPA and Mg(OH)2, respectively. Both hydrolysis products were negative in several in vitro genotoxicity test systems, without and with metabolic activation. For DPA bioaccumulation is not likely to occur, based on structure and associated physical-chemical characteristics. Becoming bioavailable, the substance or its metabolites are expected to be well distributed throughout the body fluids and rapidly excreted via urine (non-conjugated forms) or via faces (high molecular weight conjugated forms). Formation of toxic DPA metabolites is unlikely. Magnesium is an essential element, involved in several cellular and hormonal pathways. Absorbed by the body Mg2+ ions stored in the body and resorbed by the kidney. Only excess amounts are eventually excreted in the urine. The total body burden in an average adult (70 kg) is 25 g, equivalent to 357 mg/kg bw.