Registration Dossier

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
Study period:
31.10.1978 to 03.11.1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

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

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals 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:
Three males in total
Control animals:
no
Positive control:
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 seperate 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 resultsopen allclose all
Type:
absorption
Results:
2%
Type:
distribution
Results:
Affinity for bone (concentration of radioactivity in bone was 9 x greater than any other tissue)
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:
See Table 1

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:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
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.