Reaction mass of [[(2-hydroxyethyl)imino]bis(methylene)]bisphosphonic acid and Phosphonic acid, P-[(tetrahydro-2-hydroxy-2-oxido-4H-1,4,2-oxazaphosphorin-4-yl)methyl]-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11.09.2003-13.10.2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction Mass of [[(2-hydroxyethyl)imino]dimethylene]bisphosphonic acid and [(2-hydroxy-2-oxo-1,4,2-oxazaphosphinan-4-yl)methyl]phosphonic acid

EC Number:

911-811-2

Molecular formula:

C4H13NO7P2 and C4H11NO6P2

IUPAC Name:

Reaction Mass of [[(2-hydroxyethyl)imino]dimethylene]bisphosphonic acid and [(2-hydroxy-2-oxo-1,4,2-oxazaphosphinan-4-yl)methyl]phosphonic acid

Test material form:

solid - liquid: aqueous solution

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate, Kent, UK
- Age at study initiation: 8-12 weeks
- Fasting period before study: overnight and for 4 hours after dosing
- Housing: the animals were housed in groupd of 3 in suspended solid floor polypropylene cages furnished with woodflakes
- Diet: laboratory diet, ad libitum
- Water: ad libitum
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): minimum 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: undiluted or in distilled water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 mg/ml

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

Doses:

300 mg/kg, 2000 mg/kg

No. of animals per sex per dose:

3F

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily. individual body weights were reccorded prior to dosing and seven and fourteen days after treatment or at death.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: The gross pathological examination consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. the appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

approximate LD50

Effect level:

500 - 1 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: An extrapolation to 100% pure substance would give 250 – 500 mg/kg, based on 50% aqueous solution of the multiconstituent (~50:50 linear:cyclic substance).

Mortality:

Two animals treated at a dose level of 2000 mg/kg were found dead or killed in extremis two hours or one day after dosing. There were no deaths at a dose level of 300 mg/kg.

Clinical signs:

other: Signs of systemic toxicity noted at a dose level of 2000 mg/kg were hunched posture, ataxia, decreased respiratory rate, gasping, laboured and noisy respiration, loss of righting reflex, piloerection, ptosis, pallor of the extremities and red/brown staini

Gross pathology:

Abnormalities noted at necropsy of the animal that was found dead two hours after dosing were haemorrhagic lungs, dark liver, dark kidneys, haemorrhage of the non-glandular region of the stomach and severe haemorrhage of the gastric mucosa and small and large intestines. Abnormalities noted at necropsy of the animal that was killed in extremis one day after dosing were haemorrhage of the gastric mucosa and gaseous stomach and small and large intestines. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Other findings:

None reported.

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

An acute oral LD50 value between 500-1000 mg/kg (equivalent to 250-500 mg/kg pure substance) was reported in a study carried out according to an appropriate OECD guideline and in compliance with GLP.