Tetrasodium (1-hydroxyethylidene)bisphosphonate

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

04.03.1985 to 02.04.1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Tetrasodium (1-hydroxyethylidene)bisphosphonate

EC Number:

223-267-7

EC Name:

Tetrasodium (1-hydroxyethylidene)bisphosphonate

Cas Number:

3794-83-0

Molecular formula:

C2H4Na4O7P2

IUPAC Name:

tetrasodium (1-hydroxyethane-1,1-diyl)bis(phosphonate)

Test material form:

liquid

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton-Dutchland Laboratory animals
- Age at study initiation: 8 weeks
- Weight at study initiation: Males: 2.2-2.7 kg. Females: 2.5-2.7 kg
- Fasting period before study: No
- Housing: Individually, in suspended stainless steel cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 15 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 60-70
- Humidity (%): 30-70
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 19.03.85 To: 02.04.85

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: aqueous solution, administered undiluted.

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorsal area of the trunk
- % coverage: 10% of body surface area
- Type of wrap if used: Impervious plastic sleeve


REMOVAL OF TEST SUBSTANCE
- Washing (if done): test sites wiped free of excess test substance
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3.8 ml/kg

Duration of exposure:

24 hours

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

Five

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Viability: Twice daily. Clinical signs: 1, 2, and 4 hours after dosing and then daily for 14 days. Body weights: Pretest, immediately prior to dosing and days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: Macroscopic examination of all animals.

Statistics:

None

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Remarks on result:

other: Presumed equivalent to >1650 mg active salt/kg bw (IUCLID 4)

Mortality:

One female died on Day 13. However, macroscopic examination revealed signs of intestinal disease that was not thought to be related to the test substance. All other animals survived to the end of the observation period.

Clinical signs:

other: In all surviving animals there were some occurrences of oral and nasal discharge. Most animals had severe dermal effects at the dose site (necrosis followed by eschar formation and/or exfoliation of the eschar tissue), which persisted throughout the obse

Gross pathology:

The female that was found dead had gross abnormalities suggestive of mucoid enteritis. Apart from the presence of dermal lesions, there were no abnormal findings in the other animals.

Other findings:

None reported.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

In a well-conducted acute dermal toxicity limit test, conducted according to a protocol that was similar to OECD 402, but not to GLP, the dermal LD50 for Dequest 2016 was >5000 mg/kg bw (IUCLID 4 reviewer comment: presumed equivalent to >1650 mg active salt/kg bw) in the rabbit.

Executive summary:

In a well-conducted acute dermal toxicity limit test, conducted according to a protocol that was similar to OECD 402, but not to GLP, 5000 mg/kg bw of Dequest 2016 was applied to the skin of New Zealand white rabbits (5/sex) under an occlusive dressing, for 24 hours. After the 24 hour exposure period excess test substance was wiped off the test site. Animals were then observed for 14 days for signs of toxicity, and body weights were measured prior to dosing and on days 7 and 14. All animals were examined macroscopically. One female died on Day 13. However, macroscopic examination revealed signs of intestinal disease that was not thought to be related to the test substance. All other animals survived to the end of the observation period. In all surviving animals there were some occurrences of oral and nasal discharge. Most animals had severe dermal effects at the dose site (necrosis followed by eschar formation and/or exfoliation of the eschar tissue), which persisted throughout the observation period. Most animals had slight weight losses at Days 7 and/or 14. The female that was found dead had gross abnormalities suggestive of mucoid enteritis. Apart from the presence of dermal lesions, there were no abnormal findings in the other animals. The LD₅₀ was determined to be >5000 mg/kg bw.