(1-hydroxyethylidene)bisphosphonic acid, potassium salt

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978-10-30 to 1980-11-04

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Reason / purpose for cross-reference:

read-across source

Type:

distribution

Results:

small amount of test substance found in bones 0.033% in total skeleton; 0.0065% after test period

Details on absorption:

After 4 weeks 0.069 mg HEDP/kg bone (1.1 µg absolute) was found in the skeleton. This is equivalent to 0.033% of the substance administered. After 104 weeks, the amount in the skeleton was 0.0065% of the overall intake. As the radioactive levels of all organs and tissue samples with the exception of bone and intestine were only slightly above the limit of detection, the amount of HEPD absorbed from drinking water was apparently low.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study was conducted to determine the possible cumulative effects of ¹⁴C HEDP administered in drinking water over 2 years.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Sodium Salts of (1-Hydroxyethylidene)bisphosphonic acid (2-3 Na:1)

EC Number:

701-238-4

Molecular formula:

HEDP-2Na C2H6Na2O7P2 HEDP-3Na C2H5Na3O7P2

IUPAC Name:

Sodium Salts of (1-Hydroxyethylidene)bisphosphonic acid (2-3 Na:1)

Test material form:

solid

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann GmbH, BOrchen

- Age at study initiation: ca. 8 weeks

- Weight at study initiation: ca 200 g

- Fasting period before study: no

- Housing: Makrolon cages
- Individual metabolism cages: no 93 animals per cage)

- Diet: Altromin Haltungsdiät, ad libitum

- Water (e.g. ad libitum): test substance was administered in water, available ad libitum. Water consumption was measured in the first and second weeks, and then every two weeks, to obtain an average daily dose and a cumulative dose.

- Acclimation period: no information

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C (test animals) 21°C (control animals)

- Humidity (%): 50% (isotope lab, test animals) 60% (control animals)

- Air changes (per hr): no information

- Photoperiod (hrs dark / hrs light): natural daylight, therefore, variable.

IN-LIFE DATES: From: approx October 4th 1978 To: November 11th 1980

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Duration and frequency of treatment / exposure:

Continuous via ad libitum drinking water over 2 years.

Doses / concentrations

Dose / conc.:

134 mg/kg bw/day

Remarks:

equivalent to daily intake 0.184 mg/kg bw

No. of animals per sex per dose / concentration:

150 male test animals, 75 controls

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: The dose used was chosen on the assumption that a certain amount (10%) can be swallowed by using a tooth-paste containing 0.5 -1% HEDP.

- Rationale for animal assignment (if not random): no information

Details on dosing and sampling:

PHARMACOKINETIC STUDY (distribution)

- Tissues and body fluids sampled: blood, tibia

- Time and frequency of sampling: every four weeks in four test animals and two control animals.

- Radioactivity of organs was determined after drying.

- X-rays were taken to determine distribution of radiation, and morphology of bones.

- Other: Test animals remaining after 106 weeks treatment were observed for another 33 weeks, and then killed. Necroscopies were carried out.

Statistics:

t-test for water and food consumption, U-test for organ weight.

Results and discussion

Main ADME results

Type:

distribution

Results:

small amount of test substance found in bones 0.033% in total skeleton; 0.0065% after test period

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After 4 weeks 0.069 mg HEDP/kg bone (1.1 µg absolute) was found in the skeleton. This is equivalent to 0.033% of the substance administered. After 104 weeks, the amount in the skeleton was 0.0065% of the overall intake. As the radioactive levels of all organs and tissue samples with the exception of bone and intestine were only slightly above the limit of detection, the amount of HEPD absorbed from drinking water was apparently low.

Details on distribution in tissues:

Very little radioactivity was detected anywhere except in the bones. About 95% of the absorbed HEDP was found in the skeleton and 3% in the liver.

Any other information on results incl. tables

X ray studies showed that there was no influence of HEDP on morphology and length of bones.

Food consumption and body weight increased slightly in comparison with the control group.

No treatment related effects were observed in the following evaluations:

macroscopical and microscopical examinations

blood chemistry (including determination of magnesium, iron and zinc in serum)

urinalysis

bone marrow smears

organ weight determination

determination of calcium and phosphor in trachaea and tibia

Table 1 Distribution of ¹⁴C after 2 year exposure to 3.3 ppm ¹⁴C-HEDP in drinking water

Organ	¹⁴C-activity in % overall intake	¹⁴C-activity, relative distribution (%)
Intestine	5.7 ± 5.4 x 10ˉ³	40.70
Bones	7.6 ± 1.2 x 10ˉ³	54.30
Thyroid gland	1.3 ± 0.2 x 10ˉ⁵	0.09
Stomach	1.0 ± 0.7 x 10ˉ⁴	0.71
Bladder	4.2 ± 1.2 x 10ˉ⁵	0.30
Liver	2.6 ± 1.1 x 10ˉ⁴	1.86
Lungs	2.1 ± 0.5 x 10ˉ⁵	0.15
Tongue	4.7 ± 4.7 x 10ˉ⁶	0.03
Kidneys	3.1 ± 0.1 x 10ˉ⁵	0.22
Testicles	4.0 ± 1.7 x 10ˉ⁵	0.28
Eyes	2.8 ± 1.9 x 10ˉ⁶	0.02
Muscles	2.2 ± 0.5 x 10ˉ⁵*	-
Spleen	6.6 ± 0.9 x 10ˉ⁶	0.05
Pancreas	2.3 ± 0.8 x 10ˉ⁵	0.16
Brain	1.0 ± 0.6 x 10ˉ⁵	0.07
Heart	5.6 ± 1.9 x 10ˉ⁶	0.04
Skin	1.7 ± 1.3 x 10ˉ⁵*	-
Sum without stomach and intestine	8.0 ± 1.1 x 10ˉ³	-
Total sum	1.4 ± 0.7 x 10ˉ²	98.9

* Tissue weight not known

Applicant's summary and conclusion

Conclusions:

In an in vivo basic toxicokinetic study, not conducted according to any OECD Test Guideline and unknown if in compliance with GLP, rats were exposed to a continuous oral intake of radio-labelled HEDP (2-2Na) in drinking water at concentrations of 134 mg/kg bw/day over a two-year period. During the test period, the amount of HEDP was 0.033 % in the total skeleton, however, by the end of the test period the proportion was 0.0065 %. The absorption in bones was approximately 0.0065% of the amount of substance consumed. It is concluded that a small proportion of HEDP administered in drinking water is absorbed from the intestinal tract and reaches the bones. The amount in the skeleton decreases after administration ceases.