Disodium phosphonate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12/2008 to 04/2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study according to OECD guideline under GLP conditions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Disodium phosphonate

EC Number:

237-249-1

EC Name:

Disodium phosphonate

Cas Number:

13708-85-5

Molecular formula:

Na2HPO3

IUPAC Name:

disodium phosphonate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): Disodium phosphonate (BRÜGGOLEN H10)
- Substance type: inorganic
- Physical state: solid
- Analytical purity: 95%
- Composition of test material, percentage of components:
- Lot/batch No.: 07090801
- Expiration date of the lot/batch: 08.09.2009
- Storage condition of test material: room temperature

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Gartenstraße 27, 33178 Borchen, Germany
- Age at study initiation: 5 to 8 weeks
- Weight at study initiation: 160 - 180 g
- Housing: open makrolon cages type 2000P (TechniPlast)
- Diet (e.g. ad libitum): Maintenance diet rat/mouse, pellets, No. 1324 (Altromin GmbH & Co. KG, 32791 Lage), ad lib.
- Water (e.g. ad libitum): Autoclaved community tap water, ad lib.
- Acclimation period: 8 days (male), 9 days (female)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +/- 3°C
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light):12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): Freshly prepared before application

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
63 mg/kg bw
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
250 mg/kg bw
Basis:
nominal in water

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1000 mg/kg bw
Basis:
nominal in water

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: In a previously performed dose range finding study with dose escalation, the test item was administered in doses up to 2000 mg/kg body mass over a time period of 19 days and produced no observable toxic effects in the test animals. In accordance with the sponsor,
1000 mg/kg was determined as high dose for the present test.

- Rationale for animal assignment (if not random):
rats were weighed individually and grouped into weight categories, the main group consisting of animals weighing between 100 g and 120 g. These were placed consecutively into prepared cages. Rats weighing more than 120 g, but not more than 140 g, and rats weighing less than 100 g, but more than 80 g, were caged alternately after the main weight group was placed.

Positive control:

No

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: once weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once weekly
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: On day 29
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On day 29
- Animals fasted: No data
- How many animals: all

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once weekly
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / unusual behaviour

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Detailed clinical signs, food and water consumption, motoric activity, and reactivity to sensory stimuli showed no remarkable abnormalities.
The mean body mass increase of all experimental groups was within normal range for rats of
this strain and age.
Analysis of haematology and serum biochemistry showed normal results in the vast majority
of parameters monitored. The only alteration in comparison to their control group occurred in the male high dose group where the level of glutamic-oxaloacetic transaminase (GOT) was
significantly lowered. GOT acts as an indicator for liver dysfunctions and could indicate
beginning liver stress.

The histomorphological examination of the selected rat organs did not reveal morphological
lesions considered to be related to the test item. No morphological differences were noted
between the groups. All microscopic findings noted in various organs of animals of the high dose group did not distinguish significantly treated rats from control animals or the
differences noted were regarded as random events. All these findings are considered to be spontaneous in nature and within the normal background pathology commonly seen in rats of
this strain and age.

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

food efficiency

gross pathology

haematology

histopathology: neoplastic

histopathology: non-neoplastic

mortality

ophthalmological examination

organ weights and organ / body weight ratios

water consumption and compound intake

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

A daily oral administration of the test item Disodium phosphonate to Wistar rats at a dose level of 63, 250 and 1000 mg/kg body mass over a time period of 28 days resulted in very few and only mild systemic and local effects in test animals treated with the high dose (1000 mg /kg) but did not produce any pathological evidence of a local or systemic toxicity of the test item.