Aluminium tridiethylphosphinate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August- September 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Objective of study:

absorption

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The solubility and availability for absorption through the gut wall (bioaccessibility) of the Phosphorus and Aluminium component of the test substance are determined in a model system that simulates the dynamic conditions in the gastro-intestinal tract (TIM-1).

GLP compliance:

no

Remarks:

not applicable for this study type; the model has been validated for use in the food/nutrition and pharmaceutical area

Test material

Test material information

Constituent 1

Radiolabelling:

no

Test animals

Species:

other: n.a., in vitro study

Details on test animals or test system and environmental conditions:

Please refer to "Details on study design"

Administration / exposure

Route of administration:

other: n.a., in vitro study

Vehicle:

other: water/artificial saliva

Details on exposure:

Please refer to "Details on study design"

Duration and frequency of treatment / exposure:

300 min.

Doses / concentrations

Remarks:

Doses / Concentrations:
9 g substance in artificial saliva and water

No. of animals per sex per dose / concentration:

n.a., TIM model used

Control animals:

other: n.a.

Positive control reference chemical:

n.a.

Details on study design:

Test system: TIM-1
The TIM-1 system consists of one gastric compartment and three small intestinal compartments maintained at body temperature (please refer to attached document 1 "scheme of TIM model"). The stomach compartment mixing takes place of the ingested contents with secreted gastric acid, enzymes (lipase, amylase and pepsin) and electrolytes (0.5 mL/min.). It is connected to the duodenum compartment by awalve simulating the pyloric sphincter ("scheme of TIM model", B) that gradually transfers chyme (meal and drug product) from stomach into the duodenum compartment. Within the duodenum the pH is increased by bicarbonate secretion. The digestion, solubilisation and release processes are continued under continuous mixing and by secretion of bile and pancreatic juice containing all relevant enzyme (1 mL/min.). After a short residence time the chyme is transported to the jejunum compartment where it is exposed to a higher pH. In this compartment the bile salt concentration is decreased by removal of the bile salts. Digested components, dissolved drug and other low molecular weight compounds are removed by a specific membrane system from the lumen through dialysis (10 mL/min., "scheme of TIM model", M). The same processes take place in the ileum compartment under a slightly elevated pH level. The undigested and un-dissolved compounds were emptied from the ileum compartment according an exponential curve with halftime of 150 min. and collected in a vessel. This ileum efflux is regarded as material that enters the large intestine in vivo ("scheme of TIM model", H).

Details on dosing and sampling:

please refer to "Any other information"

Statistics:

None

Results and discussion

Preliminary studies:

none

Main ADME results

Main ADME results 1

Type:

absorption

Results:

0.1% of the administered Al amount corresponding to 0.008% of the complete substance dose

Main ADME results 2

Type:

absorption

Results:

26.6% of the administered P amount

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Please refer to "any other information on results incl. tables"

Details on distribution in tissues:

n.a.

Details on excretion:

n.a.

Metabolite characterisation studies

Metabolites identified:

no

Any other information on results incl. tables

Intake

The endogenous intake of aluminium originating from the total secreted gastric electrolyte solution (incl. enzymes), pancreatic juice, bile and small intestinal electrolyte solutions was approx. 0.1 mg (0.066 mg). The endogenous intake of phosphorus was 18 mg. The content of aluminium and phosphorus in the substance was determined on the basis of 75.4 g aluminium/ kg substance and 260.5 g phosphorus/kg substance, respectively. These concentrations were used to calculate the intake of aluminium and phosphorus in the TIM system from a 9 gram dose of the substance.

Aluminium and phosphorus intake in the control experiment and from administered dose testsubstance: 

		Amount (mg)
Endogenous intake	Al P	0.1 18.1
Dose from Testsubstance	Al P	678.4 2344.6

The endogenous intake of aluminium and phosphorus was negligible compared to the doses coming from the testsubstance.

Recovery

Experiments were performed successfully with good recoveries for aluminium and phosphorus. After administration of 678.4 mg aluminium from the testsubstance, 98.1 mg of the administered amount was recovered from all samples. The recovery of the administered dose of 2344 mg phosphorus was 104.5%.

Only in the control experiment a recovery below 90% was determined for aluminium; possibly due to the sample concentrations around and below the detection level (LOQ and LOD) of the analytical method.

Bioaccessibility from endogenous intake

Aluminium sample concentrations from the dialysate fractions in the control experiment were below the LOD. Thus, no bioaccessible aluminium was determined.

For phosphorus approx. 11 mg became bioaccessible from endogenous intake. A baseline was generated and used to correct the results from the testsubstance experiment.

Bioaccessibility from the testsubstance, please refer to attached document ("Document 3_Bioaccessibility of aluminium and phosphorus")

The absolute (mg) and relative (% of dose administered) (cumulative) bioaccessible fractions of aluminium and phosphorus from the testsubstance have been corrected for the endogenous contribution of phosphorus. No correction for the endogenous contribution of aluminium was required.

After administration of 678.4 mg aluminium from the testsubstance, 0.1% of the administered dose (0.7 mg) was bioaccessible, 50.6% was emptied from the ileum compartment and 47.4% was retained in the compartments of the TIM-system as non-bioaccessible fractions. For phosphorus the bioaccessible fraction from a 2344 mg dose was 26.3% (617.8 mg). From this dose was 39.0% emptied from the ileum and 39.2% was recovered from the compartments at the end of the experiment. These fractions can be regarded as non-bioaccessible.

Table: Aluminium and phosphorus recovered from TIM from the endogenous intake (0.1 mg and 18.1 mg) and from the administered dose of testsubstance (678.1 mg and 2344.7 mg).

		Control (% of endogenous intake)		DEPAL (% of dose testsubstance)
		Aluminium	Phosphorus	Aluminium	Phosphorus
Total bioaccessibility*		0.0	62.1	0.1	26.3
Ileum efflux		5.8	5.2	50.6	39.0
Residues**		29.7	23.2	47.4	39.2
Total recovery		35.5	90.5	98.1	104.5
* Bioaccessibility
Jejunum		0.0	50.6	0.0	12.5
Ileum		0.0	11.5	0.1	13.8
** residues + rinse
Stomach compartment		0.0	0.3	23.8	23.9
Duodenum compartment		0.0	9.9	2.8	2.8
Jejunum compartment		29.7	8.8	9.3	6.5
Ileum compartment		0.0	4.2	11.5	5.9

The ileum compartment showed a higher dialysed amount compared to the jejunum from the substance. The circumstances of the ileum (higher pH value compared to jejunum) and the prolonged exposure time to GI luminal conditions may enhanced the dissolution process of phosphorus and aluminium.

Applicant's summary and conclusion

Conclusions:

The bioaccessibility of aluminium and phosphorus under the conditions of the TIM model (fasted adult human) was determined to be 0.1% and 26.3% of the administered aluminium and phosphorus dose, respectively.

Executive summary:

The solubility and availability for absorption through the gut wall (bioaccessibility) of the Phosphorus and Aluminium component of the test substance are determined in a model system that simulates the dynamic conditions in the gastro-intestinal tract (TIM-1).

Dynamic gastrointestinal model, TIM-1

The TNO in vitro gastrointestinal models simulate in high degree the successive dynamic processes in the stomach and the small intestine (TIM-1 system). This system is a unique tool to study the stability, release, dissolution, absorbtion and bioconversion of nutrients, chemicals, bioactive compounds and pharmaceuticals in the gastrointestinal (GI) tract. The model has been validated for the simulation of physiological conditions within the lumen of the GI tract in the food and nutrition area as well as in the pharmaceutical area. The results obtained in the TIM system showed very good resemblance with the results obtained in studies with humans and animals for drugs and formulations.

Conclusion

The endogenous intake of aluminium and phosphorus was negligible compared to the doses coming from the substance. Bioaccessible aluminium and phosphorus from the endogenous intake were 0 mg and 11.2 mg, respectively. After administration of 678.4 mg aluminium from the substance, 0.1% of the administered aluminium dose (0.7 mg aluminium and corresponding to 0.008% of the complete substance dose) was bioaccessible, 50.6% was emptied from the ileum compartment and 47.4% was retained in the compartments of the TIM-system. as non-bioaccessible fractions. For phosphorus, the bioaccessible fraction from a 2344 mg dose was 26.3% (617.8 mg). From this dose was 39.0% emptied from the ilem and 39.2% was recovered from the compartments at the end of the experiment. These fractions can be regarded as non-bioaccessible.