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Endpoint:
dermal absorption 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:
other: The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.
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
Radiolabelling:
yes
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: 175 to 225 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
Type of coverage:
semiocclusive
Vehicle:
water
Duration of exposure:
72 hours
Doses:
- Concentration: 6.1 mg/ml
- Dose volume: 0.1 ml, which contained 2.31 microCi.
- Rationale for dose selection: None given
No. of animals per group:
Three male animals in total
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: No data
- Method of storage: No data

APPLICATION OF DOSE: Using Eastman 910 adhesive, a contoured glass ring was glued to the middle of the back of each animal. The ring was 3.6 cm diameter.

TEST SITE
- Preparation of test site: Shaved
- Area of exposure: back
- % coverage: No data
- Time intervals for shavings or clipplings: No data

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes: A porous glass disk was fitted over the skin inside the glass ring. This permited air circulation over the test site, but prevented loss of the test substance by flaking or ingestion.

REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: After 72 hours
- Washing procedures and type of cleansing agent: No

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
Signs and symptoms of toxicity:
no effects
Dermal irritation:
no effects
Absorption in different matrices:
- Non-occlusive cover + enclosure rinse: None reported
- Skin wash: None reported
- SKin adjacent to test site: 0.007 ± 0.002 (mean and SD)
- Skin test site: 89 ± 2% (mean and SD)
- Blood: 0.01 ± 0.01µg/g (mean and SD)
- Carcass: 0.5 ± 0.5% (mean and SD)
- Urine: 0.02 to 2% (mean 0.8%)
- Cage wash + cage wipe: 0.1 ±0.1 (mean and SD)
- Faeces: <=0.01%
- Expired air (if applicable): None reported
- Serial non-detects in excreta at termination: No

- Liver: none detected
- Kidneys: 0.01 ± 0.01% (mean SD)
- Gonads: none detected
- Plasma: none detected
- Muscle: 0.01 ±0.01 µg/g
Total recovery:
- Total recovery: 90%
- Recovery of applied dose acceptable: Accepted as low, but reasonable
- Results adjusted for incomplete recovery of the applied dose: Apparently not
- Limit of detection (LOD): No details
- Quantification of values below LOD or LOQ: No details
Dose:
0.1 ml
Parameter:
percentage
Absorption:
< 1 %
Remarks on result:
other: 72 hours
Conversion factor human vs. animal skin:
None

Table 1 Average excretion (% of dose ± SD)

  0 -24 h  24 -48 h  48 -72 h  Total 
Urine  0.7 ± 0.6   0.02  ± 0.01  0.01 ±0.01  0.8  ± 0.7
Feces   0.003  ± 0.003  None detected  None detected  0.0 ± 0.0

Total recovery: 90 ± 3%

Conclusions:
In a dermal metabolism study (pre-GLP; reliability score 2), less than 1% of a dermally applied dose (0.1 ml) of neutralised DTPMP was absorbed over a 72 hour exposure period. Most (89 %) of the applied dose was recovered from test site. Total recovery was 90%.
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12.11.1991 to 16.07.1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Objective of study:
toxicokinetics
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
Only one dose tested.
GLP compliance:
yes
Radiolabelling:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- 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


ENVIRONMENTAL CONDITIONS
- 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
Route of administration:
oral: gavage
Vehicle:
water
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


HOMOGENEITY AND STABILITY OF TEST MATERIAL: No data
Duration and frequency of treatment / exposure:
Single dose (animals killed ten days later)
Dose / conc.:
150 mg/kg bw/day
Remarks:
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:
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:
no
Positive control:
None
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.


METABOLITE CHARACTERISATION STUDIES
- 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
Statistics:
Data were presented as the mean ± the standard error of the mean (SEM).
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). 
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 5 hr (urinary)
Test no.:
#1
Toxicokinetic parameters:
half-life 2nd: 70 hr (urinary)
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 5.3 hr (whole body)
Test no.:
#1
Toxicokinetic parameters:
half-life 2nd: 299 hr (whole body)
Metabolites identified:
yes
Details on metabolites:
URINARY METABOLITES (24 hr sample) Parent compound = 25.1%, N-methyl derivative = 45.9% , Unidentified = 28.6% (no further details)

Table 1 Summary of urinary and faecal elimination.

 Day  Faecal elimination (%)  Urinary elimination (%)
 1


84.32

 

1.016

 2

 9.448

0.056

 3

 0.34

 0.019

 4

 0.031

 0.013

 5 -10

 0.242

 0.0342

Table 2 Summary of blood:tissue ratios at Day 10

 Tissue

 Ratio

 Tibia

 191

 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

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



AUTORADIOGRAPHY
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.)

Conclusions:
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 and 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 found 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.

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
Objective of study:
other: absorption, distribution and excretion
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
Radiolabelling:
yes
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
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
Dose / conc.:
47 mg/kg bw/day
Remarks:
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
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.
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
Metabolites identified:
not measured

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 

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.

Description of key information

The available information suggests that only minor amounts of sodium DTPMP are absorbed after ingestion (limited by physicochemical interactions within the gut) or skin contact (limited by hydrophilic nature). The kinetics for DTPMP are expected to be similar to those for the related phosphonic acids ATMP and HEDP for absorption, distribution, metabolism and excretion. There are also not expected to be any major differences between animals and humans for these parameters.

Key value for chemical safety assessment

Absorption rate - oral (%):
2

Additional information

Based on the available knowledge and data for phosphonic acids (DTPMP, HEDP and ATMP), no major differences are expected to exist between animals and humans with regard to the absorption, distribution and elimination of phosphonic acid compoundsin vivo. Also, based on physicochemical properties, the toxicokinetics of the salts of DTPMP are not expected to be different to those of the parent acid. Therefore the following information and predictions are applicable to the acid and salts. With regard to DTPMP ammonium salt, the toxicokinetics of ammonia area discussed below.

Absorption

Oral

The physicochemical properties of phosphonic acid compounds, notably their high polarity, charge and complexing power, suggests that they will not be readily absorbed from the gastrointestinal tract. This is supported by experimental data which confirm that absorption after oral exposure is low, averaging 2-7% in animals and 2-10% in humans. In a study by Procter and Gamble (1978) approximately 2% of a dose of sodium DTPMP was absorbed from a gavage dose, and 98% of the dose was excreted in feces within 72 hours of dosing.

Gastrointestinal pH is a major determinant influencing uptake, and is relatively acidic in the stomach (range: pH 1 - 4) and slightly more alkaline in the intestine (pH 4 - 7). The number of ionisations of the phosphonic acid moiety increases with increasing pH, rising from 1 - 2 at low pH (i.e. stomach) to 4 - 6 at more neutral pH (reflective of conditions in the intestine). The negative charge on each molecule also increases with each ionisation, further reducing the already low potential for uptake. Stability constants for the interaction of phosphonic acids with divalent metal ions are high, and indicate strong binding, especially at lower pHs. Complexation of a metal with a phosphonic acid would produce an ion pair of charge close to neutral which might favour absorption; however the overall polarity of the complex would remain high thereby counteracting this potential. Overall, these considerations indicate that ingested phosphonic acid compounds will be retained within the gut lumen.

Dermal

DTPMP is too hydrophilic to be absorbed through the skin. In a dermal absorption study (Procter and Gamble, 1978a, Reliability 2), 89% of the applied radioactivity (0.6 mg/kg bw) was recovered from the test site 72 hours after application to rat skin, with negligible amounts in faeces (< 0.01%) and minor amounts in urine (< 2% ) and carcass (<1.5%).

Inhalation

The vapour pressure of DTPMP is extremely low (<10E-08 Pa). Consequently, inhalation of DTPMP vapour is not possible. It is possible that a dust (from solid) or aerosol (from aqueous solution) of DTPMP could be inhaled. The potential particle size distributions that workers and consumers could be exposed to for these forms of DTPMP are not currently known. However, particle size distribution studies on the sodium salt of DTPMP indicate that any dust generated would be non-inhalable. In addition, the very high water solubility of this substance suggests that absorption will be low.

Distribution

In oral and dermal studies conducted by Procter and Gamble (1978) the concentrations of DTPMP in all tissues was extremely low, due to the low overall absorption (Table 5.1.2). In the oral study it was shown that most test substance was distributed to the bone, and this tissue had nine times more DTPMP than any other organ or tissue.

In studies on other phosphonic acids, ATMP and HEDP, bone appears to be a specific site for deposition of phosphonic acidsin vivo. Blood/tissue ratios demonstrate an approximate 80 to 200 fold increase in the concentration of phosphonic acids in rat sternum, tibia and femur after gavage exposure compared to that present in blood (Monsanto, 1995), with whole body radiography indicating preferential deposition in the epiphyseal plate of the long bones (Monsanto, 1995). A dose-dependent increase in radiolabel was observed in tibia and mandible in rats following gavage administration of 0.5 to 1000 mg/kg bw phosphonic acid. Bone imaging following 2 and 4 hour intravenous administration of radiolabelled DTPMP in rabbits (Subramanianet al., 1975) and rats (Goeckeleret al., 1978) confirms that DTPMP is preferencially distributed to bone, but that concentrations in the bone marrow are low in comparison with the bone and comparable with other tissues such as muscle, kidney and liver (Table 1).

Table 1: Distribution of DTPMP in tissues

Tissue

Distribution following oral administration (μg/kg) Procter and Gamble (1978)

(species: rat)

Distribution following 2h intravenous administration

(% dose/g) (2h)

Goeckeler (1987)

(species: rat)

 

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

(species: rabbit)

 

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

(species: rabbit)

Radiolabel

carbon

153-Sm

85-Sr

113m-In

Blood

0.05 ± 0.05

74

0.7

0.4

Plasma

0.03 ± 0.02

Not determined

Not determined

Not determined

Average bone

2.9 ± 0.79

30

8.1

4.8

Marrow

Below limit of detection

Not determined

0.3

0.2

Muscle

Below limit of detection

0.9

0.2

0.04

Kidney

0.17 ± 0.03

0.4

0.9

2.3

Liver

0.11 ± 0.02

0.3

0.3

0.2

Testes

0.05 ± 0.007

Not determined

Not determined

Not determined

Metabolism

There are no data on the metabolism of DTPMP. Metabolism of ATMPin vivoappears limited. Of the proportion of an oral dose excreted in urine, 25% is present as parent substance, approximately 50% as N-methyl derivative and the remainder as an unidentified product (Monsanto, 1995). Conversion of orally administered PACs to carbon dioxide by the rat has been variously reported as 0% (Monsanto, 1995), 0.2% (Michaelet al., 1972) or 10% (Henkel KgaA, 1983a), with 0.4% conversion described in humans (Procter and Gamble, 1978).

Excretion
Information is available on the elimination of14C-DTPMP (neutralised sodium salt) following oral or dermal administration to SD rats. In an oral toxicokinetics study using SD rats and with14C-DTPMP (neutralised sodium salt), 98% of a gavage dose (10 mg/kg bw, 7 μCi/kg bw), was excreted in the feces within 72 hours (Procter and Gamble, 1978). Of the remaining dose 1.3% was found in urine (the majority within 24 hours) and 0.4% in expired CO2. Faecal elimination of unabsorbed material predominates after ingestion (up to 90% of dose). Following dermal application, the majority of the absorbed dose was excreted in urine within 24 hours of the start of exposure.For ATMP, renal clearance of any material absorbed from the gut is rapid, with urinary half-lives of 5 hours and 70 hours reported. This second phase of excretion may represent mobilisation of material initially sequestered by bone, since deposition studies have shown preferential accumulation of these substances in the epiphyseal plate and other regions of the long bonesin vivo

In a well designed and reported study, Monsanto (1995) demonstrated that faecal excretion was the principal route of elimination following gavage administration of14C-ATMP to male rats (150 mg/kg bw; 28.76 μCi/kg bw); 74% of the dose eliminated in 24 hours, 83% at 48 hr, up to a maximum 84% at 10 days. Trace amounts of radioactivity were present in urine (approx. 1% of dose) and blood, tissues and carcass (total approx. 0.3%) but not in exhaled air. Overall mean recovery from all sources was 85.9%. In contrast, renal clearance predominated after i. v. injection (15 mg/kg bw; 1.93 μCi/kg bw), with 46% of the dose recovered in urine 6 hours post-dosing, rising to 50% after 24 hours (maximum 53% accounted for over 10 d). Overall mean recovery was 88.9%. Approx. 4 to 5% of the dose was eliminated via faeces, while blood, tissues and carcass contained a total of 23% of the dose. Based upon relative urinary excretion after gavage and i. v. administration, gastrointestinal uptake was calculated as 2.15%. Kinetic analyses indicate that ATMP is excreted in a biexponential manner by the rat, with urinary half-lives of 5 hours or 70 hours after oral exposure, and 2 hours or 127 hours after i. v. treatment (Monsanto, 1995).

DTPMP ammonium salts

The toxicokinetics of ammonia have been described in the ammonia SIAR (2007): “After uptake into a biological system the salts in the ammonia category will dissociate directly into ammonium ion and the corresponding anions, i. e. phosphate, thiosulfate and sulfate. The anions will enter the body electrolyte pool, and are not expected to play a significant toxicological role at low doses. After intestinal absorption, ammonium ions are converted to urea in the liver, and subsequently excreted in urine (within 6 hours). The ratio of ammonium ion to neutral ammonia is about 100 in blood of normal pH range (WHO, 1986).”

ATMP-H

ATMP-H is used for read-across for reproductive and developmental toxicity, therefore information on the toxicokinetics of ATMP is relevant to support the read-across.

14C-labelled ATMP was administered to male Sprague-Dawley rats, the rats were killed ten days later (Hotz, 1995). 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 of14C-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 administration.

Discussion of trends in the DTPMP category

The available information suggests that only minor amounts of sodium DTPMP are absorbed after ingestion (limited by physico-chemical interactions within the gut) or skin contact (limited by hydrophilic nature). The kinetics for DTPMP are expected to be similar to those for the related phosphonic acids ATMP and HEDP for absorption, distribution, metabolism and excretion. There are also not expected to be any major differences between animals and humans for these parameters.