[[(phosphonomethyl)imino]bis[ethylenenitrilobis(methylene)]]tetrakisphosphonic acid, ammonium salt

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

no guideline followed

Principles of method if other than guideline:

¹⁵³Sm-labeled DTPMP was injected into the tail vein of male rats. Two hours after injection the animals were sacrificed and tissues were obtained for analysis.

GLP compliance:

no

Radiolabelling:

yes

Remarks:

¹⁵³Sm

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Weight at study initiation: 160-220 g

- Housing: each rat was housed individually in a cage for 2 hours

Route of administration:

intravenous

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Sm₂O₃ was obtained as 99.06 % enriched ¹⁵²Sm. The ¹⁵³Sm was prepared by neutron irradiation using a thermal flux of 8.5 x 10¹³ n/cm² sec and a resonance flux of 1.7 x 10¹² n/cm² sec. A weighed amount of Sm₂O₃ was flame scaled into a quartz vial under vacuum and welded into aluminium can. Following irradiation the sample was opened, dissolved in 1-4 N HCl and brought to a stock concentration of approximately 1.2 x 10⁻³ M with deionized water. To form each ¹⁵³Sm complex 25-80 mg/ml of ligand were used. The amount of ligand used to achieve quantitative complex formation was first dissolved in deionized water followed by the addition of concentrated base. The ¹⁵³Sm stock and carrier solutions were added and the final samarium concentration was 3x 10⁻⁴ M with a specific activity of 1 to 10 mCi/ml (37-370 MBq/ml). The pH was adjusted to >10 and the solution heated to 60 °C for 30 min to facilitate complexation. After heating the pH was adjusted to 7.0 with 4-5M HCl.

Duration and frequency of treatment / exposure:

2 hours

Remarks:

Doses / Concentrations:
1.2 x 10⁻³ M with deionized water.
50-100 µL were administered to the animals.

No. of animals per sex per dose / concentration:

No data

Control animals:

not specified

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, blood 1ml , plasma, femur, cage washes, bile
- Time and frequency of sampling: at 2 hours post injection
- The samples were counted using an inverted Nal(T1) thyroid detector

Type:

distribution

Results:

30 % of ¹⁵³Sm-labeled DTPMP was distributed to the average bone tissue

Type:

excretion

Results:

70 % of ¹⁵³Sm-labeled DTPMP was excreted in the urine

Details on distribution in tissues:

30 % skeletal uptake was observed following injection of Samarium-153 DTPMP. Moderate skeletal uptake of the test substance.

Details on excretion:

Over 70% of Samarium-153 DTPMP was excreted in the urine. It clears from blood and other soft tissues.

Toxicokinetic parameters:

half-life 1st: Samarium-153 46.8 h

Metabolites identified:

not measured

Table 1: Distribution of ¹⁵³Sm-labeled DTPMP

Tissue	Distribution following 2h intravenous administration (% dose/g) (2h) Goeckeler (1987) (species: rat)
Radiolabel	153-Sm
Blood	74
Plasma	Not determined
Average bone	30
Marrow	Not determined
Muscle	0.9
Kidney	0.4
Liver	0.3
Testes	Not determined

Conclusions:

The study reports that DTPMP (neutralised; administered by intravenous injection) is moderately distributed to skeletal tissue and rapidly cleared from blood and soft tissues into urine (70% within two hours of injection).

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

no guideline followed

Principles of method if other than guideline:

¹¹³m-In-labeled DTPMP was injected intravenously to adult albino rabbits. One to three hours after injection the rabbits were imaged in the posterior projection with a scintillation camera. Organ distribution of radiolabel was determined after the animals were sacrificed from 1 to 4 hours after injection.

GLP compliance:

no

Radiolabelling:

yes

Remarks:

¹¹³m-In and ⁸⁵Sr

Species:

rabbit

Strain:

other: albino

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 3.5 - 5 kg
- Age at study initiation: adult

Route of administration:

intravenous

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: ¹¹³m-In or ¹¹¹In with 25-50 mg of the desired phosphonates in a volume of 4-5 ml. The pH was adjusted to 7.5-8.0 with dilute (0.1 N) sodium hydroxide or dilute (0.1 N) HCl as required since phosphonates salts dissolved in water exhibited high pH as expected and the initial pH of the mixture varied depending on the volume of the acidic indium solution. The preparation was sterilized by membrane filtration through 0.22-micron-size filters. The amount of free indium in the preparation was determined by paper electrophoresis.

Duration and frequency of treatment / exposure:

1 to 4 hours after administration

Remarks:

Doses / Concentrations:
3-5 mCi of ¹¹³m-In and 2-5 mg of DTPMP

No. of animals per sex per dose / concentration:

No data

Positive control reference chemical:

µCi of ⁸⁵Sr was used as biological standard

Type:

distribution

Results:

8.1 % of DTPMP was distributed to average bones

Type:

excretion

Results:

70 % of DTPMP was excreted in the urine at 4 hours post-administration

Details on distribution in tissues:

The liver and soft tissue concentration of the indium complexes was lower than the ⁸⁵Sr concentration. The bone marrow concentration was low. The bone-to-blood, bone-to-marrow and bone-to-muscle ratios were comparable to those for ⁸⁵Sr.

Details on excretion:

At 4 hours post-administration, almost 70 % of DTPMP complex was excreted in the urine.

Toxicokinetic parameters:

half-life 1st: 100 min

Metabolites identified:

not measured

Table 2: Distribution of ¹⁵³Sm-labeled DTPMP

Tissue	Distribution following 4h intravenous administration (% dose/1% body weight) Subramanian (1975) (species: rabbit)
Radiolabel	85-Sr	113m-In
Blood	0.7	0.4
Plasma	Not determined	Not determined
Average bone	8.1	4.8
Marrow	0.3	0.2
Muscle	0.2	0.04
Kidney	0.9	2.3
Liver	0.3	0.2
Testes	Not determined	Not determined

Conclusions:

The study reports that DTPMP (administered by intravenous injection) selectively concentrates in the skeleton of experimental animals and has fast blood clearance into urine (70% of administered dose in 4 hours).

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

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

Reason / purpose for cross-reference:

read-across: supporting information

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 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

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 / 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 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.

Reference 4

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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 or test system 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%.

Description of key information

The available information suggests that only minor amounts of sodium DTPMP-xNH4 are absorbed after ingestion (limited by physicochemical interactions within the gut) or skin contact (limited by hydrophilic nature). 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 data, no major differences appear to exist between animals and humans with regard to the absorption, distribution and elimination of phosphonic acid compounds in vivo. The toxicokinetics of the sodium, potassium and ammonium salts of DTPMP are not expected to be different to those of the parent acid. Therefore the following information and predictions are applicable to these salts.

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.

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.

In a study by Procter and Gamble (1978) approximately 2% of a dose of neutralised DTPMP-H was absorbed from a gavage dose, and 98% of the dose was excreted in feces within 72 hours of dosing.

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. 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 DTPMPH 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-H than any other organ or tissue.

Bone imaging following 2 and 4 hour intravenous administration of radiolabelled DTPMP-H in rabbits (Subramanian et al., 1975) and rats (Goeckeler et al., 1978) confirms that DTPMP is preferentially 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)	Distribution following         4h intravenous administration (% dose/1% body weight) Subramanian (1975)
				Subramanian (1975) (species: rabbit)	(species: rabbit)
Radiolabel	14-C		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	Belowlimit detection	of	Not determined	0.3	0.2
Muscle	Belowlimit detection	of	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 ATMP in vivo appears limited. Of the proportion of an oral dose excreted in urine, 25% is present as parent substance, approx. 50% as N-methyl derivative and the remainder as an unidentified product (Hotz et al., 1995). Conversion of orally administered PACs to carbon dioxide by the rat has been variously reported as 0% (Hotz et al., 1995), 0.2% (Michael et 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 of ¹⁴C-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.

 

Reference

Henkel KgaA (1983a) Unpublished data, Archive No 830091. Cited in European Chemicals Bureau IUCLID Data Sheet for CAS No 6419-19-8.

Hotz, KJ, Warren, JA, Kinnett, ML and Wilson, AGE (1995) Study of the pharmacokinetics of absorption, tissue distribution and excretion of ATMP in Sprague-Dawley rats. Unpublished report, Ceregen (a unit of Monsanto Company Environmental Health Laboratory) St Louis, MO, Report Number MSL 14475, 6 December 1995.

Michael, WR, King, WR and Wakim, JM (1972) Metabolism of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) in the rat, rabbit, dog and monkey. Toxicol Appl Pharmacol, 21, 503 - 515.

Procter and Gamble (1978) Unpublished data, Report ECM BTS 476, E-8218, MVL-YE 205, European Chemicals Bureau IUCLID Data Sheet for CAS No 15827-60-8.