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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988-01-27 to 1988-02-10
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report date:
1988

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
legacy study
Principles of method if other than guideline:
- Principle of test: To determine the acute oral toxicity of MK-0217 in young adult male and female rats.
- Short description of test conditions: Rats were administered a fixed amount of a concentrated solution of the test substance orally and then observed for up to 14 days.
- Parameters analysed / observed: Physical signs of systemic toxicity, mortality and body weight.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid hydrate
EC Number:
680-378-7
Cas Number:
138624-11-0
Molecular formula:
C4H15NO8P2
IUPAC Name:
(4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid hydrate
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and batch No.of test material: Sponsor and #002, #003

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Diluted to 0.5% and 5% solutions in dilute aqueous NaOH.

FORM AS APPLIED IN THE TEST (if different from that of starting material)
0.5% and 5% solution in dilute aqueous NaOH as the base compound.

Test animals

Species:
rat
Strain:
other: Cr1:CD(SD) BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Wilmington, MA
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 4 to 6 weeks
- Weight at study initiation: 80 to 154 grams
- Fasting period before study: 23 hour fasting period prior to treatment
- Housing: Hanging steel cages (16" x 10" x 7"), 4 per/cage
- Diet (e.g. ad libitum): Certified Purina lab chow ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controlled
- Humidity (%): Controlled
- Air changes (per hr): Controlled
- Photoperiod (hrs dark / hrs light): 8/16

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: dilute aqueous NaOH
Details on oral exposure:
VEHICLE
- Concentration in vehicle:5.0% w/w solution
- Justification for choice of vehicle: Acts as the base compound for the salt with a factor = 1.07

MAXIMUM DOSE VOLUME APPLIED:
23 mL
Doses:
500, 600, 845, 1099, 1428 mg/kg bodyweight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Once a day
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs and body weight
Statistics:
The 95% confidence interval was calculated by method of Probit Analysis.

Results and discussion

Preliminary study:
None
Effect levelsopen allclose all
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 626 mg/kg bw
Based on:
act. ingr.
95% CL:
>= 419 - <= 779
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 552 mg/kg bw
Based on:
act. ingr.
95% CL:
>= 35 - <= 727
Mortality:
Deaths occurred in about 90 minutes to 6 days. No sex difference in toxicity was apparent. This compound can be considered slightly to moderately toxic based on the results of these acute studies.
Clinical signs:
Within 30 minutes of drug administration decreased activity was seen at all dose levels. Ataxia was seen at the highest dose level (1428 mg/kg). Tremors were seen at the highest dose level in the male rats. During the first post dosing week small weight losses were noted in a few survivors in the female rats.
Body weight:
During the first week following drug administration scattered body weight losses of a small magnitude were noted in most of the studies. However, weight gains resumed during the second post drug week.

Any other information on results incl. tables

Other tests were conducted simultaneously to determine the results of administering the test substance to rats via IV and to mice via oral and IV routes. These tests reached the conclusion that IV was 20 times more toxic in mice and 10 times more toxic in rats. The LC50 for oral mouse was 1280 mg/kg bodyweight for males and 966 mg/kg bodyweight for females. The LC50 for IV mouse was 48.4 mg/kg bodyweight for males and 51.1 mg/kg bodyweight for females. The LC50 for IV rat was 21.1 mg/kg bodyweight for males and 40.2 mg/kg bodyweight for females. The 95% percent confidence intervals for the IV route LC50 values were calculated by method of C.S.Weil., and the 95% confidence interval for the oral route LC50 values was calculated via Probit analysis.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
This test substance was determined to be a category 4 acute oral toxicity based on GHS criteria.