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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:
Indium-113m-Labeled Polyfunctional Phosphonates as Bone Imaging Agents
Author:
Subramanian G, McAfee JG, Rosenstreich M, Coco M.
Year:
1975
Bibliographic source:
J Nucl Med. 1975 Nov; 16(11):1080-4; http://jnm.snmjournals.org/content/16/11/1080.long

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
¹¹³m-In-labeled DTPMP was injected intravenously to adult albino rabbits. One to three hours after injection the rabbits were imaged in the posterior projection with a scintillation camera. Organ distribution of radiolabel was determined after the animals were sacrificed from 1 to 4 hours after injection.
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:
[(bis{2-[bis(phosphonomethyl)amino]ethyl}amino)methyl]phosphonic acid
Test material form:
not specified
Radiolabelling:
yes
Remarks:
¹¹³m-In and ⁸⁵Sr

Test animals

Species:
rabbit
Strain:
other: albino
Sex:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 3.5 - 5 kg
- Age at study initiation: adult

Administration / exposure

Route of administration:
intravenous
Duration and frequency of treatment / exposure:
1 to 4 hours after administration
Doses / concentrations
Remarks:
Doses / Concentrations:
3-5 mCi of ¹¹³m-In and 2-5 mg of DTPMP
No. of animals per sex per dose / concentration:
No data
Positive control reference chemical:
µCi of ⁸⁵Sr was used as biological standard

Results and discussion

Main ADME resultsopen allclose all
Type:
distribution
Results:
8.1 % of DTPMP was distributed to average bones
Type:
excretion
Results:
70 % of DTPMP was excreted in the urine at 4 hours post-administration

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
The liver and soft tissue concentration of the indium complexes was lower than the ⁸⁵Sr concentration. The bone marrow concentration was low. The bone-to-blood, bone-to-marrow and bone-to-muscle ratios were comparable to those for ⁸⁵Sr.
Details on excretion:
At 4 hours post-administration, almost 70 % of DTPMP complex was excreted in the urine.
Toxicokinetic parameters
Toxicokinetic parameters:
half-life 1st: 100 min

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 2: Distribution of ¹⁵³Sm-labeled DTPMP

Tissue

Distribution following 4h intravenous administration (% dose/1% body weight) Subramanian (1975)

(species: rabbit)

Radiolabel

85-Sr

113m-In

Blood

0.7

0.4

Plasma

Not determined

Not determined

Average bone

8.1

4.8

Marrow

0.3

0.2

Muscle

0.2

0.04

Kidney

0.9

2.3

Liver

0.3

0.2

Testes

Not determined

Not determined

Applicant's summary and conclusion

Conclusions:
The study reports that the polyfunctional phosphonate DTPMP selectively concentrates in the skeleton of experimental animals and has fast blood clearance.