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Administrative data

Link to relevant study record(s)

Reference
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
Reason / purpose for cross-reference:
read-across: supporting information
Objective of study:
toxicokinetics
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
Radiolabelling:
yes
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
Route of administration:
oral: drinking water
Vehicle:
water
Duration and frequency of treatment / exposure:
Continuous via ad libitum drinking water over 2 years.
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.
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.
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.

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

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.

Description of key information

There are no toxicokinetic data available for HEDP potassium salt, therefore all data were read-across from HEDP sodium salt.

In the key in vivo basic toxicokinetic study (reliability score 2), 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-Na in drinking water at concentrations of 134 mg/kg bw/day over a two-year period. It is concluded that a small proportion of HEDP administered in drinking water is absorbed in the intestinal tract and reaches the bones. The amount in the skeleton decreases after administration ceases (Henkel, 1986a).

There is no available key dermal absorption study for HEDP.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
5
Absorption rate - dermal (%):
0.5
Absorption rate - inhalation (%):
5

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. Uptake and elimination of HEDP (2-3Na) by humans is generally consistent with that seen in animals. The toxicokinetics of the sodium and potassium salts of HEDP are not expected to be different to those of the parent acid, as the salts are well water soluble and the dissociation is mainly dependent on the ambient pH in the gastrointestinal tract.

 

During in vivo toxicity studies the local pH and ionic conditions within the stomach and gastrointestinal (GI) tract dominate the speciation of the phosphonate, irrespective of the form originally dosed. At a defined pH, a salt will behave no differently to the parent acid, at identical concentration of the particular speciated form present, and will be fully dissociated to yield HEDP acid and salt. Hence some properties for a salt (in contact with water or in aqueous media) can be directly read across (with suitable mass correction) to the parent acid and vice versa (see CSR Section 1 for mass correction values). In the present context the effect of the alkaline metal counter-ion (sodium/potassium) will not be significant and has been extensively discussed in the public literature. In biological systems and the environment, polyvalent metal ions will be present, and the phosphonate ions show very strong affinity to them. Therefore, read-across within the HEDP category is considered appropriate.

Therefore, the following information and predictions are applicable to these salts.

 

The physicochemical properties of phosphonic acid compounds, notably their high polarity, charge and complexing power, suggest 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 the key in vivo basic toxicokinetic study (reliability score 2), not conducted according to any OECD Test Guideline and compliance with GLP unknown, rats were exposed to a continuous oral intake of radio-labelled HEDP (2-3Na) 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 (Henkel, 1986a).

 

In a supporting in vivo basic toxicokinetic study (reliability score 2), not conducted according to any guideline and pre-GLP, 10 osteoporotic female patients (age 53 - 76 years) were administered a daily oral dose of HEDP (2-3Na) in a concentration of 20 mg/kg bw/day for 6-12 months. Mean absorption of HEDP (2-3Na) was approximately 10%, with an effective retained dose of approximately 1.6 mg/kg bw/day (Heaney and Saville, 1976).

 

In a basic toxicokinetic study (reliability score 2), not conducted according to any OECD Test Guideline and compliance with GLP unknown, radiolabelled HEDP (2-3Na) was administered to rats in a single concentration of 0.3 mg/kg by oral gavage and thereafter, administration of milk to non-fasted or fasting rats occurred. Intestinal absorption was less than 1% in all groups. The majority of the ingested substance was eliminated in the faeces (Henkel, 1986b).

 

In a supporting intestinal absorption study (reliability score 2), not conducted according to any OECD Test Guideline and pre-GLP, radiolabelled HEDP (2-3Na) was administered to humans in single doses and it was found that the majority of the ingested substance was eliminated in the faeces. Intestinal absorption was less than 1% in all groups. The excretion of radioactivity in the urine was largely completed after the first day (Oesterreichisches Forschungszentrum, 1986).

 

In a supporting intestinal absorption study (reliability score 2), not conducted according to any OECD Test Guideline and not in compliance with GLP, the intestinal absorption of HEDP (2-3Na) was investigated in male and female humans by single doses of 0.1, 1 or 5 mg/kg bw/day. The intestinal absorption was 1.47-2.65% and the excretion of the test substance in faeces were 62.7 to 83%. Elimination of the majority of the absorbed substance in the urine occurred within 1 day (Probanaurbereitung im Foschungszentrum, 1986).

 

In a supporting absorption study (reliability score 4), not conducted according to any OECD Test Guideline and pre-GLP, nine male volunteers ingested 5 or 30 mg/kg bw of unlabelled HEDP (2-3Na) for 2-3 weeks. In conclusion, the subjects ingesting 5 mg/kg bw had an intestinal absorption of 3.35% whereas those ingesting 30 mg/kg bw had an intestinal absorption of 7.19% (Recker & Saville, 1973).

 

In supporting basic toxicokinetic studies in rats (reliability score 2), not conducted according to any OECD Test Guideline and pre-GLP, it was concluded that absorption of HEDP (2-3Na) after oral administration in the rat is <10%. Approximately half of the absorbed substance is excreted in urine, and the remainder deposited in the skeleton. There is virtually no enterohepatic recirculation. Disposition is essentially similar following single or repeated exposure (Michael et al., 1972a).

 

In a basic toxicokinetic study (reliability score 2), not conducted according to any guideline and pre-GLP, beagle dogs were administered 20 or 50 mg/kg bw/day of HEDP (2-3Na). Approximately 15 - 20% of an intragastric dose was absorbed, primarily from the stomach. Higher levels present in bone from younger dogs reflects increased skeletal remodelling (Michael et al., 1972b).

 

In a basic toxicokinetic study (reliability score 2), not conducted to an OECD Test Guideline and pre-GLP, monkeys were administered 20 or 50 mg/kg bw HEDP in single doses. It is concluded that 91-97% of the absorbed test substance was excreted in faeces, with an absorption between 1-10% of the administered dose (Michael et al., 1972c).

 

In a supporting absorption study (reliability score 4), not conducted according to any OECD Test Guideline and pre-GLP, ten male human volunteers were administered an oral tablet in single doses of 5 x 200 mg radiolabelled with 14C-etidronate. The oral bioavailability of HEDP (2-3Na) was estimated to be 2.25% based on the urine outputs up to 24 or 96 hours. No further details are available (Gural, 1984).

 

In a basic toxicokinetic study (reliability score 4), not conducted according to any OECD Test Guideline and pre-GLP, rats were administered HEDP (2 -3Na) in single doses of 0.5, 5, 10, 50 or 200 mg/kg and thereafter observed for 72 hours. For the fed rats, the absorption was 1.28 - 2.62% for the whole dose range. The fasted rats absorbed approximately 33% more than the fed rats. A clearly increased absorption rate of approximately 13% could be observed for the fasted rats in the highest dose group of 200 mg/kg. The fed rats adsorbed approximately 2.7% of the absorbed amount to the skeleton whereas the fasted rats adsorbed approximately 8.8%. Absorbed HEDP which was not adsorbed to the bones was mainly renally eliminated. In conclusion, fasted rats have a higher absorption rate at a dose of 200 mg/kg than rats fed prior to administration regardless of concentration (Henkel, 1980).

 

In a supporting intestinal absorption study in humans (reliability score 4), not conducted according to any OECD Test Guideline and not in compliance with GLP, it was found that the excretion of HEDP (2-3Na) into urine following a single dose was <1% of the ingested dose (Henkel KGaA, 1986).

 

In a limited human investigation of the excretion of HEDP (reliability score 4), not conducted according to any OECD Test Guideline and pre-GLP, the authors conclude results support weak intestinal uptake of HEDP (2-3Na) with high urinary excretion and sustained retention within the non-blood compartment(s) of the body following a single dose (Caniggia & Gennari, 1977).

 

In a basic toxicokinetic study (reliability score 4), not conducted according to any OECD Test Guideline and pre-GLP, rabbits were administered 50 mg/kg of 14C HEDP (2-3Na) in single doses by oral gavage. It was concluded that less than 4% of a single gavage dose was absorbed. In total, 87% of the absorbed test substance was excreted in the urine (Michael et al., 1972d).

 

In an in vivo basic toxicokinetic study (reliability score 4), not conducted according to any OECD Test Guideline and pre-GLP, four rats were administered 50 mg/kg (calculated as HEDP acid; 4 ml aqueous solution) HEDP (2-3Na) in single doses by oral gavage to 4 rats. Of the applied dose of HEDP 2-3Na), 5.98% were absorbed enterally within 72 hours, not accounting for the enterohepatic circulation. Additionally, 81% were excreted via the faeces and 4.24% via the urine (Henkel, 1978).

 

In an in vivo basic toxicokinetic study (reliability score 4), not conducted according to any OECD Test Guideline and pre-GLP, radiolabelled HEDP 2-3Na) was administered once intravenously to rats and excreted urine was collected. After 3 days, the animals were euthanised and the tibiae were dissected. A considerable amount of the applied radioactivity was excreted via the urine: 37.9% after application of 10 µg/kg and 36.0% after application of 1 µg/kg. In conclusion, there is no indication that the application of very small amounts of HEDP leads to a highly increased adsorption to the bones (Henkel, 1986c).

 

Dermal

In a dermal absorption study (reliability score 2), not conducted according to any OECD Test Guideline and pre-GLP, a solution of 1% of HEDP (2-3Na) with 14C labelled CA 2 was applied in a single dose to the shaved back skin of male rats. Following 48 hours, 0.46% of the applied radioactivity was absorbed, indicating a poorly absorption. The main route of elimination was via faeces. Most of the absorbed amount (0.34%) could be found in the remaining carcass (excluding the skin of the application area) at the end of the test (Henkel, 1982).

 

Inhalation

The vapour pressure of HEDP is extremely low (<10E-08 Pa). Consequently, inhalation of HEDP vapour is not possible. It is possible that a dust (from solid) or aerosol (from aqueous solution) of HEDP could be inhaled. The potential particle size distributions that workers and consumers could be exposed to for these forms of HEDP are not currently known. However, the very high water solubility of this substance suggests that absorption will be low. In case of aerosol formation (spraying applications), droplets of water are typically in the range of 50 -100 µm, which is higher than the respirable fraction (5 -7 µm) or the inhalable fraction (10 -15 µm). Conservatively, an inhalation uptake of 5% is taken into account and used for the derivation of an inhalation DNEL.

 

Metabolism

No data are available on the metabolism of HEDP.