Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
The study is considered reliable without restriction as it allows to evaluate the adsorption of the substance, in accordance with the mandatory test reported in Regulation EC 1907/2006 Annex VII-X, without requiring additional animals sacrifice. In order to assess the substance adsorption it was chosen to measure the barium and the iron content in urine samples (barium was determined in plasma samples too) by means of an elemental analysis (ICP).

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2011
Report Date:
2011
Reference Type:
study report
Title:
Unnamed
Year:
2011

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
equivalent or similar to
Guideline:
EU Method B.36 (Toxicokinetics)
Principles of method if other than guideline:
In order to evaluate the adsorption of the substance when it is administered by oral route, urine and plasma samples were collected during an acute oral toxicity test on rats. The animals were administered with a single dose; two dose levels were investigated (0, 300, 2000 mg/kg bw). Overall, the urine and plasma samples were collected from seven animals.
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
The animal weight at the beginning of the test ranged from 230 to 262 g.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Duration and frequency of treatment / exposure:
Animals were administered with a single dose of test material
Doses / concentrations
Remarks:
Doses / Concentrations:
0 mg/kg bw
300 mg/kg bw
2000 mg/kg bw
No. of animals per sex per dose:
1 animal/female/0 mg/kg bw
1 animal/female/300 mg/kg bw
5 animals/female/2000 mg/kg bw
Control animals:
yes
Details on study design:
In order to evaluate the adsorption of the substance when it is administered by oral route, urine and plasma samples were collected during an acute oral toxicity test on rats. The animals were administered with a single dose; two dose levels were investigated (0, 300, 2000 mg/kg bw). Overall, the urine and plasma samples were collected from seven animals.
The barium concentration was determined in urine and plasma samples by means of an ICP analysis.
Since the plasma samples are quantitatively limited because only one sampling per animal could be made (more sampling might have affected the reliability of acute toxicity test) the iron content in the plasma could not be determined.
Details on dosing and sampling:
Following the substance administration (oral route by gavage) plasma samples (2 ml) were collected by the tail vein of animals at 12 hours while urine samples were collected at 0 (pre-dose), 12, 24, 48 hours. Iron concentration measurements were carried out on all urine samples but not on plasma samples which were quantitatively inadequate for the analysis.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
The barium concentration was measured in plasma samples collected at 12 hours after the exposure. It ranged from 10 to 122 ug/L in the plasma of animals treated with 2000 mg/kg while the control animal showed a plasma concentration equal to 16 ug/kg.
Type:
excretion
Results:
The urinary barium concentrations, which were measured in urine samples harvested from 0 to 48 hours, were very low. Only the 0,04% of the ingested barium (as barium hexaferrite) was excreted by the urine.
Type:
excretion
Results:
The urinary iron concentrations, which were measured in urine samples harvested from 0 to 48 hours, were negligible. Only the 0,01% of the ingested iron (as barium hexaferrite) was excreted by the urine.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The amount of barium and iron recovered in urine is negligible if compared to the administered dose and it is not relevant for pharmacological and toxicological purposes.
Furthermore, the barium amount is not found in stoichiometric ratio with the iron in all urine samples; therefore, the barium and the iron traces cannot be related to the barium hexaferrite presence in urine. They would be related to analytically undetectable impurities of barium oxide and iron oxide.

The barium concentration found in plasma samples is very low as compared with the control. Since it is measured on spot sample (all collected at 12 hours) no further speculation is possible.

Metabolite characterisation studies

Metabolites identified:
no

Applicant's summary and conclusion

Conclusions:
Interpretation of results:
Considering the barium and the iron amount recovered in urine and the barium concentration measured in plasma, it can be concluded that the barium hexaferrite is not adsorbed by oral route. It has to be noted that barium and iron in urine do not reflect the stoichiometric ratio of these two elements in barium hexaferrite. It cannot be excluded that a little amount of both barium and iron can be present in the substance as non reacted materials, available for systemic absorption. Since the solubility and consequently the possible absorption rate is greater for barium oxide than for iron oxide, this can explain the difference observed between barium and iron urinary excretion (barium 0,04% and iron 0,01% of the administered dose, respectively).