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Diss Factsheets

Administrative data

basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
12.11.1991 to 16.07.1993
2 (reliable with restrictions)
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 Type:
study report
Report date:

Materials and methods

Objective of study:
Test guideline
equivalent or similar to guideline
OECD Guideline 417 (Toxicokinetics)
Only one dose tested.
GLP compliance:

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): Dequest 2000 (aminotrimethylenephosphonic acid)
- Substance type: Phosphonic acid
- Physical state: Solid
- Purity test date: No data
- Lot/batch No.: Lot NBP 4704283 (Lot NBP 4704290 for second sample)
- Expiration date of the lot/batch: No data
- Radiochemical purity (if radiolabelling): radiochemical purity 87% (second sample 78%)
- Specific activity (if radiolabelling): 0.488 uCi/mg ((0.402 uCi/mg for second sample )
- Locations of the label (if radiolabelling): Trimethyl carbon
- Expiration date of radiochemical substance (if radiolabelling): No data
- Stability under test conditions: No data
- Storage condition of test material: No data

Test animals

Details on test animals or test system and environmental conditions:
- Source: Charles River Portage or Charles River Kingston
- Age at study initiation: 51 to 81 days
- Weight at study initiation: 242 to 393 g
- Fasting period before study: No data
- Housing: Individual stainless steel cages with wire mesh bottoms, or Roth-type metabolism cages.
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 14-31 days

- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 27.12.1991 To: 16.07.1993

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Test substance was dissolved in distilled water.All dosing solutions were aliquoted by weight, diluted and weighed portions were counted by Liquid Scintillation Counting to determine concentration and specific activity.

VEHICLE : Distilled water
- Justification for use and choice of vehicle (if other than water): N/A
- Concentration in vehicle: No data
- Amount of vehicle (if gavage): 1 to 2 ml
- Lot/batch no. (if required): No data
- Purity: No data

Duration and frequency of treatment / exposure:
Single dose (animals killed ten days later)
Doses / concentrations
Doses / Concentrations:
Males: 150 mg/kg bw (Received dose was calculated by weighing syringe plus dosing needle before and after use. Specific activity of dosing solution = 1073600 dpm/mg; equivalent amount of radioactivity = 28.76 uCi/rat).
No. of animals per sex per dose / concentration:
Males: four
A further two rats (dosed as above) were sacrificed 1 d and 10 d post-treatment for whole-body autoradiography. 
A further two rats were dosed as above and were sacrificed after 72 hours. This group was used to determine whether radioactivity was present in expired CO2, but was not discussed in the study report.
Control animals:
Positive control reference chemical:
Details on study design:
- Dose selection rationale: No data
- Rationale for animal assignment (if not random): No data
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, tissues, cage washes
- Time and frequency of sampling: Urine, faeces and cage washes at 24 hour intervals after dosing until sacrifice, in-life blood samples were collected at 15 and 30 minutes, 1, 2, 4, 6, 12 and 24 hours after dosing, then daily thereafter. At sacrifice blood samples were obtained and the following tissues and organs obtained: liver, kidneys, bone (femur), spleen, skeletal muscle, bone marrow. Gastrointestinal contents were collected by flushing the intestinal tract with saline. All samples were stored frozen at -20oC.

- Tissues and body fluids sampled (delete / add / specify): urine
- Time and frequency of sampling: 24 hours after treatment.
- From how many animals: (samples pooled or not) Not clear from study report
- Method type(s) for identification: HPLC
- Limits of detection and quantification: No data
Data were presented as the mean ± the standard error of the mean (SEM).

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The percent of ATMP absorbed was calculated to be approximately 2.2 %.
Urine = 1.1% Cage wash = 0.305% Carcass = 0.209% Tissue/organs = 0.055% Gut contents = 0.022% Blood = 0.0006% Plasma = 0.0005%
Details on distribution in tissues:
Approximately 0.2 % of the dose was found in the carcass of animals dosed orally. Very little ATMP-derived radioactivity remained in any of the other analysed tissues ten days after dosing. When comparing the tissue to blood levels (see Table 2), the bones had the highest tissue to blood ratios.
Details on excretion:
The faeces was the major route of elimination (84%), while urine (1.1%) contributed much less (see Table 1). No significant amount of 14C was present in exhaled carbon dioxide (no further details). 
Toxicokinetic parametersopen allclose all
Test no.:
Toxicokinetic parameters:
half-life 1st: 5 hr (urinary)
Test no.:
Toxicokinetic parameters:
half-life 2nd: 70 hr (urinary)
Test no.:
Toxicokinetic parameters:
half-life 1st: 5.3 hr (whole body)
Test no.:
Toxicokinetic parameters:
half-life 2nd: 299 hr (whole body)

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
URINARY METABOLITES (24 hr sample) Parent compound = 25.1%, N-methyl derivative = 45.9% , Unidentified = 28.6% (no further details)

Any other information on results incl. tables

Table 1 Summary of urinary and faecal elimination.

 Day  Faecal elimination (%)  Urinary elimination (%)













 5 -10



Table 2 Summary of blood:tissue ratios at Day 10





 Femur  158
 Bone marrow  104
 Sternum  75.6
 Carcass  7.81
 Gut contents  3.63
 Kidneys  2.61
 Spleen  1.8
 Liver  1.1
 Blood  1.0
 Erythrocytes  0.792
 Muscle  0.644
 Plasma  0.02

Individual total recovery = 81.85 - 88.55%
Mean total recovery = 85.90% (SEM = 1.62)

At 24 h, the major regions of localisation of 14C were:
- gut contents
- stomach contents
- nasal turbinates
- bone and bone marrow
Radioactivity also observed in the kidney (no other tissues) and throughout all bones of the body (most intense in
epiphyseal plate of the long bones and in nasal turbinates).

At 10 d post-dose, intense localisation still apparent in bone, especially the epiphyseal plate of the long bones. Some low level deposition of 14C was present in stomach lining and the kidneys (no other tissues affected). (The authors note that this pattern is consistent with that reported for EHDP.)

Applicant's summary and conclusion

Interpretation of results (migrated information): no bioaccumulation potential based on study results
In a well conducted and reported toxicokinetics study (reliability score 1) ATMP was poorly absorbed and rapidly eliminated after oral administration.Bone was the only tissue that demonstrated significant accumulation of ATMP-derived radioactivity.
Executive summary:

In a well conducted and reported toxicokinetics study (reliability score 1) 150 mg/kg bw 14C-labelled ATMP was administered to male Sprague-Dawley rats, the rats were killed ten days later. Whole-body autoradiography was used to determine tissue distribution, and metabolism was studied using HPLC analysis. Total recovery was 86%. The majority of the dose (84.2%) was excreted in the faeces and only 1.1% was excreted in the urine. The amount of radioactivity in the urine was used to determine the extent of absorption by comparing urinary excretion between orally and intravenously dosed rats. Using this approach, absorption following administration of 14C-labelled ATMP was shown to be approximately 2.2%. The initial and terminal urinary half-lives were approximately 5 and 70 hours, respectively. The initial phase whole-body elimination half-life was 5.3 hours and the terminal half life was 299 hours. HPLC analysis of urine samples collected 24 hours after administration revealed the presence of the parent compound, the n-methyl derivative and an unidentified metabolite. Approximately 0.06% of the dose was found in the bone (femur, tibia and sternum) and 0.21% of the dose was found in the carcass. The overall tissue distribution confirmed that the highest levels of radioactivity were in the bone. No significant signs of localisation in other tissues were evident ten days after administation. Overall ATMP was poorly absorbed and rapidly eliminated after oral administration. The bone appeared to be the only tissue that demonstrated any significant amount of accumulation of ATMP-derived radioactivity.