[[(phosphonomethyl)imino]bis[hexamethylenenitrilobis(methylene)]]tetrakisphosphonic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

31.10.1978 to 03.11.1978

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:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Objective of study:

other: absorption, distribution and excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

To provide preliminary information about the absorption, distribution and excretion of a compound after its administration to animals.

GLP compliance:

no

Test material

Test material information

Constituent 1

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:

liquid

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Age at study initiation: No data
- Weight at study initiation: 196 to 203 g
- Fasting period before study: yes, overnight and four hours after dosing
- Housing: Metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): No data
- Acclimation period: At least four days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: 31.10.1978 to 03.11.1978

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Not reported

HOMOGENEITY AND STABILITY OF TEST MATERIAL: No details

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
1 ml (10 mg TS/ml) - dose of active 47±2 mg/kg

No. of animals per sex per dose / concentration:

Three males in total

Control animals:

no

Positive control reference chemical:

None

Details on study design:

- Dose selection rationale: None given

Details on dosing and sampling:

For 72 hours after dosing the animals were housed in metabolism cages designed to separate urine, feces and expired CO2. The rats were fitted with fecal cups. Accumulated urine and feces was collected at 24, 48 and 72 hours after application of the test substance. CO2 was collected from the rats at 8 hour intervals for 72 hours (3 samples/day/rat).

SAMPLE COLLECTION
- Collection of blood: Blood samples taken at terminal sacrifice at 72 hours.
- Collection of urine and faeces: metabolism cages and fecal cups.
- Collection of expired air: metabolism cages
- Terminal procedure: Ether
- Analysis of organs: All organs and tissues removed for analysis.

SAMPLE PREPARATION
- Storage procedure: Samples frozen until analysis.
- Preparation details: Organs and tissues rinsed with water and blotted with paper towel. Fat or connective tissue from the organs removed and placed in sample jars. Organs that have internal cavities (heart, gall and urinary bladders) cut open and rinsed with water. If the urinary bladder contained urine, this urine was rinsed into the urine 48-72 hour collection. Skin samples were taken from the back of the animals. Bone samples were taken from the femur after the bone marrow had been removed. Muscle samples were taken from the hind limb. Adipose tissue samples were taken from the area of the psoas muscle. Carcasses were then frozen with dry ice before grinding in a Wiley mill.

ANALYSIS
- Method type(s) for identification: Liquid scintillation counting
- Liquid scintillation counting results (cpm) converted to dpm as follows: No details
- Validation of analytical procedure: No details
- Limits of detection and quantification: No details

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

2%

Main ADME results 2

Type:

distribution

Results:

Affinity for bone (concentration of radioactivity in bone was 9 x greater than any other tissue)

Main ADME results 3

Type:

excretion

Results:

98% excreted in feces by 72 hours, 1.3% in urine and 0.4% in CO2.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

98% of the dose was excreted into feces, leaving 2% that was absorbed.
Total recovery: 100.6 ± 3.3%

Details on distribution in tissues:

Liver: 0.01± 0.00%
Kidneys: 0.004 ± 0.001%
Testes: 0.001± 0.000%
Carcass: 0.6 ± 0.2%
Cage wash: 0.0± 0.0%
GI tract: 0.005± 0.003%
GI wash: 0.0 ± 0.0%
Lung: 0.0009 ± 0.0001%
Spleen: 0.0002± 0.0002%
Pancreas: 0.0 ± 0.0%
Brain: 0.0 ± 0.0%
Muscle: 0.0 ± 0.0%
Bone: 2.9 ± 0.79 µg/g
Bone Marrow: 0.0 ± 0.0 µg/g
Blood: 0.05 ± 0.05 µg/g
Plasma: 0.03 ± 0.02 µg/g
Adipose: 0.0 ± 0.0 µg/g

Details on excretion:

Total excretion in urine: 1.3 ± 0.2%
Total excretion in feces: 98 ± 4%
Total excretion in CO2: 0.4 ± 0.0%

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Table 1 Average excretion (% of dose ± SD) of neutralised DTPMP following oral ingestion.

	0 -24 h	24 -48 h	48 -72 h	Total
Urine	1.2 ± 0.2	0.06 ± 0.009	0.03 ± 0.01	1.3± 0.2
Feces	94 ± 5.2	4.3 ± 1.5	0.1 ± 0.005	98 ± 4
CO2	0.4 ± 0.0 (0 -8 h); Not detected (8 -24 h)	Not detected	Not detected	0.4 ± 0.0

Applicant's summary and conclusion

Conclusions:

In an oral toxicokinetics study in rats, conducted prior to GLP (reliability score 2), 98% of the dose (oral gavage) of neutralised DTPMP was excreted in feces within 72 hours. Of the remaining dose 1.3% was found in urine and 0.4% in expired CO2. Minor quantities were found in various tissues, but the bone was found to have nine times more (2.9 ± 0.79 µg/g) than any other organ or tissue.