[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, calcium sodium salt

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was well documented and meets generally accepted scientific principles, and conducted in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Materials and methods

Principles of method if other than guideline:

the study design of i.v.dosing studies in rats and mice to examine the absorption, tissue distribution, metabolism and excretion and retention of the test compound. A total of 20 male rats and male mice were used, with 4 from each group sacrificed at 6, 24 and 96 hr and 14 and 28 days following dosing. Excreta were sampled at 8, 24,48,72,96 and 168 hours following dosing. At sacrifice tissues and organs were analysed for 14C content.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, sodium salt

EC Number:

244-742-5

EC Name:

[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, sodium salt

Cas Number:

22036-77-7

IUPAC Name:

22036-77-7

Details on test material:

Non labelled EDITEMPA (Dequest 20419) - Lot nr 176-40-4) with chemical purity of 99%.
14C labelled EDITEMPA , with radiochemical purity ranging from 92-93%.. The 14C compound had a purity ranging from 96.4 - 99 %.
The compound was dissolved in sodium hydroxide solution and if necessary the pH was adjusted to ca 7. The doses administered via IV to rats at a volume of 4 ml/kg, and in mice at a volume of 20 ml/kg via the tail vein.

Radiolabelling:

yes

Test animals

Species:

other: Rat (Sprague Dawley) and mice (B6C3F1)

Strain:

other: Sprague Dawley rats and B6C3F1 mice

Sex:

male

Administration / exposure

Route of administration:

intravenous

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

A total of 20 male rats and male mice were used, with 4 from each group sacrificed at 6, 24 and 96 hr and 14 and 28 days following dosing. Excreta were sampled at 8, 24,48,72,96 and 168 hours following dosing. At sacrifice tissues and organs were analysed for 14C content.

Doses / concentrations

Remarks:

Doses / Concentrations:
15 mg/kg

No. of animals per sex per dose / concentration:

Only males used.

Control animals:

no

Results and discussion

Preliminary studies:

Following iv administration (15 mg/kg) to rats the compound disappeared from the blood rapidly. In 2 hours only 0.4% of the dose was recovered in blood. After which 14C disapperared slowly. The distribtion t1/2 was 14 mins while the elimiation t1/2 was 67 hours. Eliimination of 14C in urine was rapid, by 8 hours 56% of the dose was excreted by this route, 12% between 8 -168 hours. Excretion in faeces was limited to 7% of the dose in 168 hours. Recovery of 14C in tissue was low even at early 6 hour sacrifice times. The spleen, bone marrow and kidneys showed higher uptake of radioactivity.
In mice elimination of 14C in urine was seen as 56% of dose eliminated by 24 hours and an additional 16% by 168 hours. Only 3% via the faeces in 168 vs 7 % in rats, suggesting a lower elimination by the biliary/intestinal routes in mice. Recovery of 14C was very low even at early times and only spleen and kidneys showed significant uptake of radioactivity.
Rats- most of administered radioactivity was recovered in bone, 55% of dose at 6hr declining to 21% by 28 days post dosing. Disappearance of EDITEMPA from the bone occurred slowly (t ½ of 20 days). The trabecular bone showed the higher 14C level than cortical bone, with disappearance from the latter occuring at a slower rate.
For mice 35% of the administered dose was recovered in bone at 6 hours, which decreased to 19% at 28 days. EDITEMAP disappeared from the bone of mice with a t ½ of 26 days. The AUC was 1393 micrograms/g. day in mice compared to 1903 micrograms/g. day in rats. The average level of EDITEMPA in bone was higher in rats than mice.
HPLC analysis of excreta indicated the presence of impurities in the sample and the increased amounts in the ecreta is probably due to preferential uptake of EDITEMPA by the bone.
In summary, these studies show that EDITEMPA has a high affinity for bone. The disappearance of 14C from bone is slow, as demonstrated by the long t ½ of 20 days (rats) and 26 days (mice). Data suggests that EDITEMPA is not metabolised to any great extent. The disposition in both mice and rats is similar. Although the levels of 14C in rats and mice were slightly different they probably do not account for any differences in biological response.

Applicant's summary and conclusion

Conclusions:

In summary, these studies show that following iv administration (15 mg/kg) to rats, EDITEMPA has a high affinity for bone. The disappearance of 14C from bone is slow, as demonstrated by the long t ½ of 20 days (rats) and 26 days (mice). Data suggests that EDITEMPA is not metabolised to any great extent. The disposition in both mice and rats is similar. Although the levels of 14C in rats and mice were slightly different they probably do not account for any differences in biological response.

Executive summary:

A total of 20 male rats and male mice were used, with 4 from each group sacrificed at 6, 24 and 96 hr and 14 and 28 days following IV dosing (15 mg/kg). Excreta were sampled at 8, 24, 48, 72, 96 and 168 hours following dosing. At sacrifice tissues and organs were analysed for 14C content. These studies show that EDITEMPA has a high affinity for bone. The disappearance of 14C from bone is slow, as demonstrated by the long t ½ of 20 days (rats) and 26 days (mice). Data suggests that EDITEMPA is not metabolised to any great extent. The disposition in both mice and rats is similar. Although the levels of 14C in rats and mice were slightly different they probably do not account for any differences in biological response.