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Diss Factsheets

Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Skeletal Localization of Samarium-153 Chelates: Potential Therapeutic Bone Agents
Author:
Goeckeler WF, Edwards B, Volkert WA, Holmes RA, Simon J, Wilson D. J.
Year:
1987
Bibliographic source:
Nucl Med. 1987 Apr; 28(4):495-504

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
¹⁵³Sm-labelled DTPMP was injected into the tail vein of male rats. Two hours after injection the animals were sacrificed and tissues were obtained for analysis.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
[[(phosphonomethyl)imino]bis[ethane-2,1-diylnitrilobis(methylene)]]tetrakisphosphonic acid
EC Number:
239-931-4
EC Name:
[[(phosphonomethyl)imino]bis[ethane-2,1-diylnitrilobis(methylene)]]tetrakisphosphonic acid
Cas Number:
15827-60-8
Molecular formula:
C9H28N3O15P5
IUPAC Name:
Diethylenetriaminepentakis(methylphosphonic acid)
Test material form:
not specified
Radiolabelling:
yes
Remarks:
¹⁵³Sm

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Weight at study initiation: 160-220 g

- Housing: each rat was housed individually in a cage for 2 hours

Administration / exposure

Route of administration:
intravenous
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Sm₂O₃ was obtained as 99.06 % enriched ¹⁵²Sm. The ¹⁵³Sm was prepared by neutron irradiation using a thermal flux of 8.5 x 10¹³ n/cm² sec and a resonance flux of 1.7 x 10¹² n/cm² sec. A weighed amount of Sm₂O₃ was flame scaled into a quartz vial under vacuum and welded into aluminium can. Following irradiation the sample was opened, dissolved in 1-4 N HCl and brought to a stock concentration of approximately 1.2 x 10⁻³ M with deionized water. To form each ¹⁵³Sm complex 25-80 mg/ml of ligand were used. The amount of ligand used to achieve quantitative complex formation was first dissolved in deionized water followed by the addition of concentrated base. The ¹⁵³Sm stock and carrier solutions were added and the final samarium concentration was 3x 10⁻⁴ M with a specific activity of 1 to 10 mCi/ml (37-370 MBq/ml). The pH was adjusted to >10 and the solution heated to 60 °C for 30 min to facilitate complexation. After heating the pH was adjusted to 7.0 with 4-5M HCl.

50-100 microliters of the ligand complex were injected into the tail veins of unanaesthetised rats. The rats were exposed to the substance for 2 hours and were then sacrificed.
Duration and frequency of treatment / exposure:
2 hours
Doses / concentrations
Remarks:
1.2 x 10⁻³ M with deionized water.
50-100 µL were administered to the animals.
No. of animals per sex per dose / concentration:
No data
Control animals:
not specified
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, blood 1ml , plasma, femur, cage washes, bile
- Time and frequency of sampling: at 2 hours post injection
- The samples were counted using an inverted Nal(T1) thyroid detector

Results and discussion

Main ADME resultsopen allclose all
Type:
distribution
Results:
30 % of ¹⁵³Sm-labelled DTPMP was distributed to the average bone tissue
Type:
excretion
Results:
70 % of ¹⁵³Sm-labelled DTPMP was excreted in the urine

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
30 % skeletal uptake was observed following injection of Samarium-153 DTPMP. Moderate skeletal uptake of the test substance.
Details on excretion:
Over 70% of Samarium-153 DTPMP was excreted in the urine. It clears from blood and other soft tissues.
Toxicokinetic parameters
Toxicokinetic parameters:
half-life 1st: Samarium-153 46.8 h

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1: Distribution of ¹⁵³Sm-labeled DTPMP

Tissue

Distribution following 2h intravenous administration

(% dose/g) (2h)

Goeckeler (1987)

(species: rat)

Radiolabel

153-Sm

Blood

74

Plasma

Not determined

Average bone

30

Marrow

Not determined

Muscle

0.9

Kidney

0.4

Liver

0.3

Testes

Not determined

Applicant's summary and conclusion

Conclusions:
The study reports that DTPMP (neutralised; administered by intravenous injection) is moderately distributed to skeletal tissue and rapidly cleared from blood and soft tissues into urine (70% within two hours of injection).